Point/Counterpoint |
From the National Heart and Lung Institute (NHLI) Division, Imperial College School of Medicine, London, United Kingdom.
Correspondence to Peter H. Sugden, DPhil, NHLI Division (Cardiac Medicine), Imperial College School of Medicine, Dovehouse St, London SW3 6LY, United Kingdom. E-mail p.sugden{at}ic.ac.uk
Key Words: myocardial hypertrophy and failure mitogen-activated protein kinase cascade calcineurin calcium movement transcription
| Introduction |
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The predominating view is that mammalian ventricular myocytes lose their capacity for cell division during the perinatal period and are thus terminally differentiated cells, although this is still a matter of some dispute (reviewed in References 6 and 76 7 ). In contrast, other cells in the heart (endothelial cells, fibroblasts, and smooth muscle cells) retain their mitotic capacity. Although ventricular myocytes are not the only cell type involved in the overall hypertrophic response, much of the ventricular enlargement or remodeling is attributable to their hypertrophy. The identities of signaling pathways that couple the demand for increased contractile power to increased myocyte growth and altered gene expression have been actively investigated for many years. Protein phosphorylation (catalyzed principally by Ser-/Thr- or Tyr-specific protein kinases) and phosphoprotein dephosphorylation (catalyzed by phosphoprotein phosphatases) play central roles in the regulation of many cellular events, including growth and cell division, and it is widely believed that these processes participate in myocyte hypertrophy.
From the broad point of view, 2 hypotheses of hypertrophy
have been proposed, which are the extrinsic and the intrinsic
hypotheses. The former maintains that myocyte hypertrophy
results from extracellular factors (Table 1
) that are either of a
neuroendocrine origin (eg, the catecholamines) or are
synthesized and released locally by the myocytes and
nonmyocytes in the heart (eg, endothelin-1 [ET-1] and
angiotensin II [Ang II]). The intrinsic hypothesis
maintains that changes originating within the myocyte are responsible
for hypertrophy. Because of its well-established role in
excitation-contraction coupling, increased
[Ca2+]i concentration has
been suggested to be an intrinsic mediator. The 2 hypotheses are not
mutually exclusive because, in the hands of some workers, extrinsic
agonists such as ET-1 increase
[Ca2+]i concentrations in
myocytes (reviewed in References 8 and 98 9 ) and, conversely,
[Ca2+]i is known
to be involved in the secretion of peptide hormones (eg, secretion of
atrial natriuretic factor [ANF] from
myocytes10 ). The problem with the
Ca2+ hypothesis is that, although
[Ca2+]i has been
implicated in the hypertrophic response,11 12 no clearly
defined coupling mechanism has been substantiated until recently. As
discussed in the accompanying article,13 the recent
elegant studies of Molkentin et al14 have provided
evidence that the Ca2+/calmodulin
(CaM)dependent phosphoprotein phosphatase calcineurin (also known as
protein phosphatase 2B) plays a significant role in myocyte
hypertrophy. The excitement generated by this finding was
demonstrated by the rapid appearance of editorials in
Science15 and Nature
Medicine.16 The problem is that there will be an
inevitable temptation to believe that the biochemical mechanisms
underlying myocyte hypertrophy and heart failure have been
elucidated in all but detail and that therapeutic intervention is now
readily at hand. Indeed, in a review of a recent manuscript that we
submitted, one reviewer made the following comment: "The authors talk
a lot about the mitogen-activated protein kinase (MAPK) pathway
and hypertrophy and omit any mention of the recent and
exciting observations about the role of Ca2+ and
calcineurin-dependent activation of NFAT [nuclear factor of
activated T lymphocytes] transcription factors in
hypertrophy. At this point, it seems likely that many of
the hypertrophic effects of the agonists used here are mediated by the
calcineurinNFAT pathway rather than the MAPK pathway." In my
opinion, this comment crystallizes the dangers that Molkentin et
al14 have unintentionally created, and I am convinced that
the issue is far from settled. There are 3 main points that I wish to
cover. First, is there evidence for the involvement of other (possibly
interacting) signaling pathways leading to hypertrophy?
Second, how convincing is the evidence for involvement of calcineurin?
Third, if calcineurin is involved, how convincing is the mechanism
proposed by Molkentin et al,14 namely
dephosphorylation of the transcription factor nuclear
factor of activated T-lymphocytes-3 (NFAT3)?
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| Experimental Investigation of Myocardial Hypertrophy |
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-actin, and ß-myosin
heavy chain (ß-MHC). Although now being superseded by BNP,
reexpression of ANF has been widely used as an index of
hypertrophy. Over 24 to 48 hours, other genes are
upregulated (ventricular myosin light chain 2, cardiac
muscle
-actin). Expression of some genes is downregulated (eg,
sarcoplasmic/endoplasmic reticulum Ca2+-ATPase 2
[SERCA2], reviewed in Reference 2121 ), whereas the expression of others
is relatively unchanged. Gene expression is regulated by the binding of trans-acting transcription factors and other cooperating proteins (eg, RNA polymerases) to cis-acting consensus recognition sequences that lie upstream (5') from the transcriptional initiation sites in genes (the promoter region) or to more distant enhancer regions. For most genes, these regions contain multiple sequences recognized by a variety of transcription factors (for a review on the heart, see Reference 2222 ), and interactions between the various DNA-bound transcription factors occur. Gene expression is most commonly studied by transient transfection of expression plasmids containing fusion genes of the 5'-upstream regulatory sequences of hypertrophic "marker" genes (eg, ANF) coupled to suitable reporter genes. This has allowed the identification of regulatory elements within the promoter regions. By cotransfecting/coinfecting suitable reporters with plasmids or adenoviral vectors encoding signaling proteins, this approach has been used to identify putative participants in the induction of hypertrophy.
One frequently ignored fact is that hypertrophy requires increased accumulation of protein (particularly of myofibrillar proteins) and increased myofibrillogenesis. Control at the level of protein turnover and sarcomeric assembly is necessary. As reviewed in Reference 1919 , hypertrophic agonists generally increase the rate of protein synthesis in the short term by increasing the peptide chain initiation (the rate-controlling step). In the longer term, ribosomal synthesis also increases. Because of the experimental difficulties in measuring protein degradation (particularly of specific proteins) with accuracy, it is not clear whether this process is also regulated. In addition, the regulation of myofibrillogenesis is also poorly understood.
Hypertrophy In Vivo
In vivo, probably the most commonly used surgical intervention
involves coarctation of the aorta, which induces a pressure-overload
hypertrophy. It is important to note that although the
aorta can be coarcted at a variety of levels to induce pressure
overload, the models may not be necessarily equivalent.23
A variety of transgenic mouse models of cardiac hypertrophy
or failure have been developed (reviewed in References 24 through 2624 25 26 ).
Although transgenic "knockouts" have been used, most studies have
involved expression of a wild-type transgene or one encoding a
constitutively active form of a protein. The transgene is
cardiospecifically expressed by placing it under the regulation of a
constitutive cardiomyocyte promoter (often the
-MHC
promoter sequence). One problem is that transgene expression is
difficult to control. In the mouse, mRNA for both
-MHC and ß-MHC
is expressed from the onset of cardiogenesis, with ß-MHC mRNA
predominating during fetal development.27 This is reversed
during the perinatal period, with a switch occurring in relative
abundances of transcripts (
-MHC mRNA:ß-MHC mRNA,
16:1). This
pattern is maintained during adult life in control mice. There are
several points here. First, because of the leakiness of the
-MHC
promoter, placing a transgene under its control may still allow
transgene expression at critical stages in cardiac development. Second,
the recapitulation of ß-MHC expression and the decline in
-MHC
expression during hypertrophy should lead to
down-regulation of transgene expression at this stage. Third,
transgenesis may modify expression of other genes through obscure
mechanisms (see, eg, References 28 and 2928 29 ). Fourth, there may be
considerable variability in phenotype and penetrance between
individuals expressing any single transgene.30 Fifth, the
phenotype is often influenced by the strain of mouse used. In
the future, it is likely that use of inducible systems will allow more
highly regulated expression of heterologous transgenes, but, even here,
transgene expression may be difficult to control uniformly.
| Before Calcineurin: Myocardial Hypertrophy and Signaling Through Protein Kinase C (PKC) and MAPK Cascades |
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GTP-binding proteins (G proteins) participate in the activation of MAPK cascades, and these can be broadly divided into 2 types: the heterotrimeric (GPCR-associated) group and the p21 small G protein superfamily, of which there are 5 subgroups (prototypically Ras, but also Rho, ADP ribosylation factors, Rab, and Ran). Of the heterotrimeric G proteins, the Gq/G11 subfamily (Gq for simplicity) has been shown most convincingly to be associated with hypertrophy. From the p21 small G protein superfamily, only the Ras and Rho subgroups (reviewed in References 41 and 4241 42 , respectively) have been examined from this standpoint. All G proteins are biologically inactive in their GDP-ligated form and become activated on exchange of GDP for GTP. Their innate GTPase activity returns them to the inactive state (the GDP/GTP cycle), but this process can be stimulated by ancillary proteins. A number of proteins also affect GDP/GTP exchange (the GPCRs in the case of heterotrimeric G proteins, stimulatory guanine nucleotide exchange factors such as Sos, and inhibitory factors for the small G proteins).
I will use ET-1 as my principal example of a hypertrophic GPCR agonist,
as there is unanimity that it is strongly hypertrophic. By binding to
heptahelical transmembrane GPCRs, agonists such as ET-1 stimulate the
dissociation of membrane-bound inactive heterotrimeric
Gq proteins [(
q
· GDP) · ß
] into
q · GTP
and ß
dimers. Both
q · GTP and
ß
dimers are potentially capable of activating phospholipase Cß
isoforms leading to the hydrolysis of membrane phosphatidylinositol
4,5-bisphosphate (PtdInsP2) to inositol
1,4,5-trisphosphate (InsP3) and diacylglycerols
(DGs). DGs are retained in the plane of the membrane, and the
DG-sensitive isoforms of PKC (principally nPKC
and nPKC
in the
rat ventricular myocyte43 44 ) translocate to
the particulate fraction (and presumably become activated).
Phorbol esters such as phorbol 12-myristate 13-acetate (PMA)
act as DG analogs and also translocate myocytic nPKC
and
nPKC
,45 46 and they are also strongly
hypertrophic.47 48 The next step(s) in the signaling
pathway is unclear, but the end result is that both ET-1 and PMA
activate membrane-bound Ras (Ras · GDP
Ras ·
GTP) (A. Chiloeches, P.H. Sugden, unpublished data, 1998).
One of the best-defined roles of Ras · GTP is its activation of
the extracellular signalregulated protein kinase (ERK) cascade
(Figure 1
), which is particularly involved in cell growth,
division, and differentiation. The ERK cascade MKKKs are members of the
Raf family (c-Raf, A-Raf, and B-Raf), the MKKs are MKK1 and MKK2, and
the MAPKs (phosphorylation motif Tyr-Glu-Thr) are ERK1
(p44-MAPK) and ERK2 (p42-MAPK). ET-1 and PMA strongly activate
all 3 stages of the ERK cascade (Raf,49 MKK1 and
-2,50 and ERKs43 50 51 ) in myocytes.
Activation of Raf involves its binding to membrane-localized Ras
· GTP and its translocation to this fraction. It is not clear whether
this interaction is sufficient to activate Raf or whether other
events such as Ser/Thr phosphorylation and/or Tyr
phosphorylation (possibly involving nonreceptor protein
Tyr kinases of the Src family52 53 ) are additionally
required. The potential for ERKs to regulate gene transcription in the
myocyte is demonstrated by the rapid appearance (within 4 minutes) of
active phospho-ERKs in nuclei of myocytes exposed to PMA (H.F.
Paterson, P.H. Sugden, unpublished data, 1998).
Depending on the criteria used, there are an additional 2 (see, eg,
Reference 3232 ) or 5 (see, eg, Reference 5454 ) subgroups of the MAPK
superfamily. The simpler classification based on the sequences of the
tripeptide phosphorylation motif will be used here. The
c-Jun N-terminal kinases (JNKs; phosphorylation motif
Thr-Pro-Tyr) and the p38-MAPKs (phosphorylation motif
Thr-Gly-Tyr) were first identified as being activated by
cellular stresses (eg, protein synthesis inhibitors,
hyperosmotic shock, and reactive oxygen species), and this is certainly
true in myocytes.55 56 57 It has also emerged that
Gq proteincoupled receptor
(GqPCR) agonists such as ET-1 are moderately
effective in activating JNKs55 and p38-MAPK57
in these cells but that PMA is a poor
activator.55 57 The upstream signaling
pathways are not as clear as in the ERK cascade, although MKKs, MKKKs,
other protein kinases, and small G proteins (particularly Rac and
Cdc42, 2 members of the Rho subfamily) are likely to be involved. As
with the ERKs, activation of JNKs and p38-MAPKs leads to
phosphorylation of transcription factors (Figure 1
) and other signaling molecules. Generally speaking, the
biological roles of the JNKs and p38-MAPKs are less clear than those of
the ERKs. In addition to their hypertrophic actions in myocytes (Table 2
), activation of JNKs has been associated with
apoptosis in nonmyocytes and
myocytes,58 59 whereas the p38-MAPKs have been associated
with both apoptosis60 and cytoprotection/cell
survival57 59 61 in myocytes (and other cells).
There is considerable evidence that activation of any of the 3 MAPK
cascades can lead to a hypertrophic response in myocytes. All 3 MAPK
subfamilies are activated by ET-1 and other hypertrophic GPCR
agonists,43 50 51 55 57 and the novel hypertrophic agonist
prostaglandin F2
62 63 has
recently been shown to activate JNKs.64
Transfection/infection of suitably constitutively activated
components of the cascades (Table 2
) leads to induction of many
features of the hypertrophic response, although myofibrillogenesis is
not always observed. Transfection/infection of "dominant-negative"
(inhibitory) mutant components of the cascades opposes the
hypertrophic actions of GPCR agonists, as does downregulation of ERKs
by antisense oligodeoxynucleotides65 or
transfection of phospho-MAPK phosphatases.66 67 It is
evident from Table 2
that there is still considerable confusion
in this area, and the reasons for the variations between experimental
groups are unclear (reviewed in Reference 3232 ). Two points should be
borne in mind. First, the degree of overexpression may mean that the
experiments have little relation to the
physiological situation. Second, the regulation of
transcription from genomic DNA may be quite different from that from
episomal (plasmid) DNA because of the influence of chromatin proteins.
In the hands of some (but not all68 69 ) investigators,
selective inhibitors of the ERK and p38-MAPK cascades
(PD98059 for the ERK cascade57 and SB203580 or SB202190
for the p38-MAPK cascade60 61 70 ) diminish the
hypertrophic response to GPCR agonists, although the interpretation of
these studies may not be simple.57 The overall conclusion
is that MAPK cascades participate in the hypertrophic response. The
ensuing steps are unclear, but it is presumed that transcription factor
phosphorylation and transcriptional activation follow,
and ET-1 certainly induces phosphorylation and
upregulation of c-Jun protein in myocytes.71 Furthermore,
the interaction of the novel transcription factor ATF6 with the
ANF promoter region, which may be responsible for inducible expression
of ANF, may be stimulated by p38-MAPKdependent
phosphorylation of ATF6.72 Despite some
anomalies,66 68 73 I personally still favor a
predominating role for the ERKs, and I regard the hypertrophic response
as an attempt at "transformation" in a terminally differentiated
cell.
In addition, activation of participating signaling molecules proximal
to the MAPK cascades leads to a hypertrophic phenotype. With
particular reference to the ERK cascade, it is clear that transient
transfection of myocytes with constitutively activated forms of
the G
q subunit,69 74 PKC
isoforms,75 76 77 Ras,78 or
Src79 80 leads to a hypertrophic response. Inhibition of
G
q signaling in transgenic mice by disruption
of coupling between the GqPCR and
Gq protein diminishes the hypertrophy
associated with pressure overload and diminishes the activation of ERKs
by GqPCR agonists.81 Except for Src
(which has not been tested), cardiospecific overexpression of each of
these signaling molecules leads to the development of cardiac
hypertrophy and heart failure in transgenic mouse
models,30 82 83 84 85 86 although some investigators have
interpreted their results as indicating that the
hypertrophy is independent of ERKs (see, eg, Reference 8484 ).
One problem with this interpretation is that ERK was only examined at
the heart failure end stage. Activation of ERKs by hypertrophic
agonists is transient,50 and they probably trigger
responses. Prolonged activation would therefore not be anticipated.
Participation of the Rho family of small G proteins (Rho isoforms
themselves [eg, RhoA], Rac, and Cdc42, reviewed in Reference 4242 ) in
hypertrophy has also been examined. In a variety of
nonmyocytic cell lines, the Rho family regulates cell morphology and
actin stress fiber assembly. In addition, Rac and Cdc42 appear to be
involved in activation of the JNK and p38-MAPK cascades, but Rho
isoforms are not thought to activate these cascades. Although
less effective than constitutively activated Ras,
constitutively activated Rac is hypertrophic.70
Signaling through Rho itself is poorly understood. Two groups of
Rho-activated protein kinases (Rho kinase/ROK
and PRK/PKN
groups) have been identified (reviewed in Reference 8787 ), the PRK/PKN
group being related to PKC (reviewed in Reference 8888 ). Recent evidence
suggests that, in addition to Ras, hypertrophy induced by
or mediated through G
q may also require
signaling through RhoA69 89 90 91 92 and that Rho kinase/ROK
may mediate this effect.92 However, it is not clear
whether hypertrophic agonists activate Rho or the various
Rho-dependent kinases.
| An Involvement of Calcineurin in Myocardial Hypertrophy and Heart Failure? |
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398]) has been described in which about two thirds
of the N-terminal region of the regulatory domain has been
deleted.95 The deleted region includes most of the
CaM-binding domain, the autoinhibitory domain, and the
C-terminal variable region, but the calcineurin B and immunophilin
(see below) binding sites are intact. Increasing the
Ca2+ concentration into the micromolar range
causes a small activation in the absence of CaM, but in the presence of
CaM, there is a highly cooperative activation of calcineurin. The role
of calcineurin B in the regulation of enzymic activity by
Ca2+ is obscure. It is essential for enzymic
activity (perhaps more so than CaM), but the suggestion is that it
fulfils a structural role.
One exciting function of calcineurin is its involvement in
NFAT-mediated T-lymphocyte activation (reviewed in References 94, 96,
and 9794 96 97 ). NFATs (reviewed in References 94 and 9794 97 ) are a family of Rel
homology transcription factors, a group that also includes nuclear
factor
B. In the inactive state, NFATs are
phosphorylated and (like nuclear factor
B) are
retained in the cytoplasm. NFATs are tightly associated with
calcineurin, and this association is apparently independent of the
phosphorylation state of NFAT. When T lymphocytes bind
to antigen-presenting cells through T-lymphocyte receptors,
cytoplasmic Ca2+ concentrations increase and
activate calcineurin, leading to NFAT
dephosphorylation (Figure 2
). This allows NFAT to migrate into the
nucleus (still complexed to calcineurin98 ), where it
upregulates the transcription of a number of genes, including those for
interleukin-2 (an autocrine growth factor in T lymphocytes) and other
lymphocyte growth factors. The increase in cytoplasmic
Ca2+ is mediated by phospholipase C
catalyzed
hydrolysis of PtdInsP2 to
InsP3, with concomitant release of
Ca2+ from intracellular stores. In addition,
muscarinic GqPCR-mediated activation of NFATs has
been described in lymphocytes and other cells.99 100 It is
not clear which protein kinases maintain NFAT in its inactive state in
the cytoplasm in any cell type, and this remains an important question.
Candidates include JNKs,101 casein kinase I
in
conjunction with MAPK/ERK kinase kinase (MEKK1, an
MKKK),102 and glycogen synthase kinase
3.103 104 Calcineurin is the target of the
immunosuppressants cyclosporin A (CsA) and FK-506 in T lymphocytes
(reviewed in References 94 and 9794 97 ). These bind to their respective
binding proteins, the immunophilins cyclophilin A and 12- and 12.6-kDa
FK-506 binding proteins (FKBP12 and FKBP12.6, respectively). The
CsA-cyclophilin and FK506-FKBP12 complexes bind to the calcineurin
heterodimer and prevent its activation. In T cells, CsA inhibits the
activation of the JNK and p38-MAPK cascades by an unknown
mechanism.105 This observation may be relevant to
hypertrophy, in which (as described above) both of these
cascades have been implicated.
|
Calcineurin and Cardiac Hypertrophy/Heart Failure
The transcription factor GATA4106 (reviewed in
Reference 107107 ) is present in adult heart (and a limited number of
other tissues) and is involved in the positive regulation of a variety
of hypertrophic marker genes, including ANF, BNP, and
ß-MHC.108 109 GATA4 interacts with other transcription
factors, and recent work has suggested that ANF expression may be
regulated by cooperative interaction of cis elements with
GATA4 and Csx/Nkx2.5.110 Csx/Nkx2.5 is a homeodomain
transcription factor that is cardiospecifically expressed into
adulthood.111 112
The recent findings of Molkentin et al14 (summarized in
Reference 1313 ) implicating a
[Ca2+]i
calcineurin
NFAT3
pathway in cardiac hypertrophy that is analogous to T-cell
activation have caused a great deal of excitement. Using a yeast
2-hybrid screen and a mouse whole-embryo cDNA library, numerous clones
encoding proteins interacting with GATA4 were isolated. The only clone
of which the identity was reported encoded NFAT3, and details of the
identities of the other proteins are eagerly awaited. However, given
that a whole embryo library was used, these species may not be relevant
to the heart. Myocytes transiently transfected with plasmids encoding
calcineurin A(1
398), NFAT3, and GATA4 dramatically increased
expression of a BNP reporter. Transfection of any 1 plasmid, or of any
2 plasmids, was much less effective. It is somewhat surprising that
calcineurin A(1
398) alone did not stimulate the BNP reporter, and
this might suggest that NFAT3 and/or GATA4 are limiting. The expression
of ANF and cardiac troponin I genes was examined, but no quantitative
details were presented. It is not clear whether myofibrillar
assembly was increased in the transfected myocytes. CsA or FK-506
reduced the increases in cell size and myofibrillar assembly of
myocytes exposed to Ang II or phenylephrine for 72 hours,
as well as the Ang IIinduced increase in ANF mRNA expression. This
result appears to differ from that of Boluyt et al,113 who
showed that FK-506 was ineffective in reducing
phenylephrine-induced increases in myocyte size.
Molkentin et al14 suggested that Ang II and
phenylephrine (and, inferentially, ET-1) increase
[Ca2+]i concentrations,
and indeed some workers have found this to be the case. This is by no
means universally accepted, especially in adult cardiac
myocytes.114 115 116 However, there is good evidence that
these agonists induce alkalosis in myocytes (reviewed in References 9,
117, and 1189 117 118 ) probably by activating the sarcolemmal
Na+/H+ exchanger (reviewed
in Reference 119119 ), a process known to be regulated by PKCs and MAPKs.
Given that Ca2+ binding to regulatory
"EF hands" proteins such as CaM and troponin C is mediated
by deprotonated acidic amino acids,120 121 alkalinization
will favor increased Ca2+ binding to its effector
proteins even in the absence of detectable increases in free
[Ca2+]i
concentrations.122 Thus, hypertrophic agonists could
activate calcineurin by raising
[Ca2+]i concentrations,
pHi, or both (Figure 2
). This is
rather a satisfying hypothesis from another point of view, because
small increases in pHi potently stimulate cardiac
protein synthesis,123 another cardinal feature of the
hypertrophic response. Myocardial hypertrophy could be
mediated through changes in the concentrations of simple ions
(Ca2+ and H+).
Transgenic Mice
Cardiomyocytic (
-MHC promotercontrolled) expression of
calcineurin A(1
398) in a number of founder lines induced a cardiac
enlargement viewed by the authors as corresponding principally to
"concentric" hypertrophy,14 the type often
found in association with pressure overload. Somewhat surprisingly,
given that the active phosphatase was targeted to myocytes, increased
cardiac fibrosis was also detected. This implies that alterations
within myocytes might induce remodeling and synthesis of the
extracellular matrix, presumably by communicating with fibroblasts and
smooth muscle cells. Details of the contractile properties of the
transgenic hearts and hemodynamic measurements were not
presented, nor were details of Ca2+
transients in single myocytes. In lymphocytes, activation of
calcineurin and translocation of NFAT is favored both by sustained
plateaux of [Ca2+]i124 and by
more rapid (1 per 1 minute)
[Ca2+]i
oscillations.125 This is quite different from
the situation in the mouse heart, in which the rate of beating is
400 per 1 minute. It is not clear whether such rapid transients lead
to activation of calcineurin, and, unfortunately, it is not feasible to
measure calcineurin activity in situ. Nor is it clear to what extent
the myocardial hypertrophy and failure in these transgenic
animals represents an accurate analog of the human disease,
given the possible disturbances in development that could occur
because of "leaky"
-MHC promoter activation (see above) with
activation of calcineurin during embryogenesis and fetal life.
Furthermore, it is not known whether pure myocyte
hypertrophy alone contributed to the cardiac enlargement,
or whether there was coexisting myocyte hyperplasia, as seen in
transgenic mice that overexpress CaM developmentally.126
It is interesting that myocytes from calcineurin A(1
398) transgenic
animals showed alterations in nuclear morphology,14
suggesting that the protein may interfere with the cell cycle.
Cardiospecific expression of constitutively activated NFAT3
(NFAT3
317, in which the N-terminal third of the molecule
encompassing the sites of phosphorylation and
calcineurin interaction is deleted) caused hypertrophy in
transgenic mice.14 In cultured myocytes, NFAT3
317
protein was localized to the nucleus, whereas the full-length protein
remained in the cytoplasm. To my mind, this represents some of
the strongest evidence that the calcineurin/NFAT3 pathway induces
myocardial hypertrophy. However, it is not clear whether
hearts from the NFAT3
317 transgenic mice were similar to those from
calcineurin A(1
398) transgenic animals, nor whether transfection of
NFAT3
317 induced a hypertrophic phenotype in cultured
myocytes. Again, the possible involvement of NFAT in cardiac
development127 should be borne in mind.
Interaction of Calcineurin, Ca2+, and MAPK
Signaling Pathways
There is clear evidence that the calcineurin/NFAT pathway
interacts with other signaling pathways. In the nucleus, NFATs interact
with the activator protein-1 (AP-1) transcription factor
complex (c-Fos/c-Jun heterodimers) to bind to the 5'-regulatory region
of the interleukin-2 gene (reviewed in References 96 and 12896 128 ), and the
crystal structure of this complex has recently been
determined.129 Since AP-1 transactivating activity is
under the control of signals emerging from the Ras superfamily and the
MAPK cascades (eg, through phosphorylation of c-Jun,
reviewed in References 130 and 131130 131 ), these signaling pathways cooperate
with the calcineurin pathway (reviewed in References 128 and 132128 132 ).
Although currently there is no experimental evidence to suggest the
existence of regulatory interaction, the promoter region of the ANF
gene contains 2 AP-1related cAMP responsive element (CRE)-like
consensus sequences (TGAGCTCA, at 555 to 549 bp and at 603 to
596 bp on the sense strand) in close apposition to 2 NFAT sequences
(consensus [A/T]GGAAA, at 541 to 536 bp on the sense strand and
at 612 to 607 bp on the antisense strand). The CRE-like sequence
binds c-Jun/ATF2 heterodimers, and (as with c-Jun) ATF2 transactivating
activity is increased by MAPK-catalyzed
phosphorylation.133 134 135 The interaction
of calcineurin signaling pathways with MAPK pathways in
hypertrophy is thus a distinct possibility (Figure 2
). In addition, there are already examples of interaction of
[Ca2+]i with the ERK and
JNK cascades in myocytes,12 136 137 and a recent article
has even suggested that the PKC
Ras
Raf
MKK1/-2
ERK pathway may
induce changes in Ca2+ transients similar to
those seen in myocardial hypertrophy and heart
failure.138 The mechanisms of these interactions remain
relatively ill defined.
Might CsA and FK-506 Be Used to Treat Cardiac
Hypertrophy and Heart Failure?
CsA has been reported to diminish the hypertrophy or
dilated cardiomyopathy seen in 3 transgenic models
involving mutations in myofibrillar proteins.139 In
addition, prophylactic administration of CsA inhibited the
development of cardiac hypertrophy after suprarenal banding
of the abdominal aorta in the rat.139 In contrast, CsA
does not prevent the cardiac hypertrophy induced by
cardiospecific expression of an activated retinoic acid
receptor,139 implying that some forms of myocardial
hypertrophy may be mediated by calcineurin-independent
signaling pathways. However, 2 separate groups have subsequently been
unable to detect any inhibitory effect of CsA or FK-506 on
pressure-overload hypertrophy induced by constriction of
the abdominal aorta in the rat140 or the transverse aorta
in the mouse.141 Although these differences may be
attributable to variations in experimental technique or to the time
course of hypertrophy in pressure-overload
models,142 they do indicate that the involvement of
calcineurin in hypertrophy in vivo has not been
unambiguously established. More importantly, from the point of view of
therapy, it is not clear whether administration of CsA during the
"decompensated" phase of hypertrophy/heart failure
(rather than prophylactic administration) is
beneficial.
CsA is a relatively toxic drug that is used clinically to counteract rejection after transplantation. In addition to problems of immunosuppression (increased opportunistic infection and skin malignancies), the drug is nephrotoxic, and this may be caused by its interference with the calcineurin-dependent regulation of convoluted tubule Na+/K+-ATPase.143 Its use is also associated with hypertension (possibly because of the nephrotoxic side effects involving renal vasoconstriction144 ), neural effects (tremor and fits), hepatotoxicity, and gingival hypertrophy/hyperplasia. A number of studies in transplant patients have examined the association of cardiac hypertrophy with the use of CsA. Although some studies have failed to detect a convincing association (eg, Reference 145145 ), others have shown that CsA may actually induce cardiac hypertrophy through its hypertensive side effects.146 147 In addition, at least 1 study has found that CsA has hypertrophic effects that are independent of its hypertensive effects.148 Although FK-506 may cause fewer side effects,144 it is more expensive than CsA. There is thus relatively little evidence that administration of immunosuppressants to human beings is antihypertrophic, and, in my view, it would be ill advised to administer them prophylactically.
Calcineurin and Specification of Skeletal Muscle Fiber
Type
Transfection of calcineurin A(1
398) into C2C12 myotubes
increases transcription of slow fiber type-specific genes through NFATs
and interacting transcription factors, and administration of CsA in
intact rats increases the proportion of fast muscle fibers in the
slow-twitch postural soleus muscle.149 Characterization of
muscle fiber composition in a suitable calcineurin A(1
398)
transgenic mouse is eagerly awaited. At first sight, the studies
might seem irrelevant to myocardial disease. However, in a canine model
of chronic heart failure, the proportion of slow-twitch fibers is
decreased.150 This could not be attributed to changes in
capillary density or muscle fiber destruction. Similar changes in fiber
type (combined with exercise intolerance) are seen in human heart
failure, although here there may also be fiber loss and changes in
capillary density (reviewed in Reference 151151 ). A therapeutic regime
that increases calcineurin activity and the content of slow-twitch
fiber type in skeletal muscle might therefore be beneficial in heart
failure patients. However, if calcineurin is involved in cardiac
hypertrophy, such a regimen could be detrimental to the
heart.
| Do Derangements in Excitation-Contraction Coupling Contribute to Cardiac Hypertrophy? |
|---|
|
|
|---|
A number of transgenic mouse lines in which proteins that participate in [Ca2+]i handling are overexpressed or "knocked out" have been developed. CaM plays a role in the regulation of cell growth and division in eukaryotic calls (reviewed in Reference 155155 ). Developmental overexpression of CaM induces myocyte hypertrophy and hyperplasia,126 with calcineurin and CaM kinase II suggested as possible targets. The excitation-contraction characteristics of these myocytes have not been investigated. Cardiospecific overexpression of calsequestrin also induces hypertrophy.29 156 Myocytes from these mice show reduced CICR from the SR, increased storage of Ca2+ in the SR, and depressed contractility. In contrast, the phospholamban knockout mouse shows positive inotropism and lusitropism (presumably because of release of the phospholamban-mediated inhibition of SERCA2 activity), but hearts are not hypertrophied.157 Equally, overexpression of SERCA2 increases cardiac contraction and relaxation but does not cause hypertrophy.28 However, reductions in cytoplasmic Ca2+ concentrations do not appear to account for the hypertrophy and hyperplasia seen in the CaM transgenic mice, since overexpression of a mutant CaM that binds Ca2+ normally but is defective in signaling to CaM targets/effectors does not induce growth responses.126 Obviously, it would be desirable to characterize Ca2+ handling in all of these transgenic models under uniform conditions, but it is unlikely that this will ever be achieved.
Is there any evidence of interaction between calcineurin, the immunophilins, and proteins involved in excitation-contraction coupling? It is believed that FKBP12 interacts with RyR1, whereas the closely related protein FKBP12.6 interacts with cardiac RyR2 (reviewed in Reference 158158 ). FKBPs may mediate anchoring of calcineurin to the RyR, and this interaction may be involved in the regulation of channel activity through phosphorylation/dephosphorylation (reviewed in Reference 9494 ). FK-506 disrupts this interaction. Interestingly, single RyR2 opening probability was increased in transgenic FKBP12 knockout mice,159 although it is not clear whether increased RyR2 opening results from the absence of FKBP12 alone or the (presumed) absence of interaction of RyR2 with calcineurin. Although the FKBP12 knockout was frequently embryonically lethal, with mice displaying severe cardiac defects, 1 mouse that survived to adulthood showed signs of heart failure and cardiomyopathy.
In addition to release through the RyR, release of [Ca2+]i from stores in the endoplasmic reticulum is regulated by the InsP3 receptor (InsP3R), which is closely related to the RyR. Although the InsP3R was initially thought to be of little importance in the cardiac myocyte (and this is probably true for regulation of contraction), more detailed studies have established the presence of InsP3R species in cardiac myocytes, and at least in the ferret myocyte, the type 2 InsP3R predominates.160 FKBP12 interacts with the InsP3R1 subtype, but it is not known whether InsP3R2 (or the InsP3R3) interacts with FKBP. However, the amino acid residues thought to be most important in binding of FKBP to InsP3R are conserved.161 These results suggest that chronic activation of calcineurin could perturb Ca2+ handling, and, if these perturbations led to defects in contraction, hypertrophy might indirectly ensue.
| Mitochondrial Permeability Transition (MPT) Pore, Calcineurin, and Cell Necrosis/Apoptosis |
|---|
|
|
|---|
1.5 kDa (reviewed in References 162
through 164162 163 164 ). The structure of the MPT pore is not understood, but it
is associated with inner-membrane adenine nucleotide
translocase,165 which exchanges intramitochondrial ATP for
cytoplasmic ADP. In the heart, opening of the MPT pore is increased by
oxidative stress and adenine nucleotide depletion,
conditions that are encountered during ischemia/reperfusion.
These situations enhance the sensitivity of the pore to
Ca2+ and increase binding of mitochondrial matrix
cyclophilin to the mitochondrial membrane in a CsA-sensitive manner.
Indeed, administration of CsA preserves mitochondrial integrity and
cardiac function under adverse conditions (see, eg, References 166
through 168166 167 168 ; reviewed in Reference 162162 ), possibly through inhibition of
MPT pore opening. Mitochondrial permeability is intimately related to necrosis and to the mitochondrial pathway of apoptosis (reviewed in References 162 through 164162 163 164 ). Apoptosis of the cardiac myocyte (reviewed in References 169 and 170169 170 ) is an area arousing a great deal of interest currently because of the putative role of the process in the development of heart failure. In the mitochondrial pathway of apoptosis, release of cytochrome c from mitochondria allows formation of a complex between cytochrome c, apoptotic protease activating factor 1, ATP/dATP, and procaspase 9. This causes aggregation of procaspase 9 and its activation through cleavage to produce active caspase 9, which in turn leads to activation of caspases 3, 6, and 7. These caspases then cleave key substrates, leading to apoptosis. The mitochondrial pathway of apoptosis is inhibited by antiapoptotic members of the Bcl-2 family (Bcl-2 itself and Bcl-XL) and is promoted by proapoptotic Bcl-2 family members (Bax and Bad). Although it does not directly allow escape of cytochrome c as such, opening of the MPT pore may be an initiating event in the mitochondrial apoptotic pathway. However, apoptotic situations involving the mitochondrial pathway that do not involve the MPT pore have been identified, and these may be related to the ability of proteins such as Bax to form membrane channels/pores.
Expression of wild-type calcineurin A and B, or of constitutively activated calcineurin A, promotes apoptosis in BHK cells (particularly in association with Ca2+ influx), and this could be opposed by coexpression of Bcl-2,171 with which calcineurin interacts.172 Although calcineurin bound to Bcl-2 retains its phosphatase activity, formation of the complex is thought to localize calcineurin to an intracellular membrane fraction at which it is unable to dephosphorylate NFATs.172 In agreement with the foregoing, CsA and FK-506 inhibit apoptosis in a lymphoma cell line.173 The mechanisms underlying the proapoptotic function of calcineurin have not been elucidated, although it is possible that dephosphorylation of Bad (Bad phosphorylation suppresses its proapoptotic function) could be important (reviewed in Reference 174174 ).
The preceding discussion suggests that some of the findings of
Molkentin et al14 could be related to the ability of
calcineurin and the MPT pore to promote cell death/apoptosis.
Postmortem hearts from calcineurin A(1
398) transgenic mice showed
signs of heart failure with dilatation and gross
fibrosis.14 Although the subject of much current debate,
it has been suggested that human heart failure might be associated with
apoptosis of the cardiac myocyte.175 176
Hypothetically, it could be argued that cardiospecific activation of
calcineurin could promote apoptosis of myocytes, and it is this
that leads to heart failure. CsA could prevent calcineurin-dependent
apoptosis and the MPT. Indeed, in endothelial
cells, CsA inhibits apoptosis by preventing mitochondrial
efflux of cytochrome c.177 One major
problem with this hypothesis is that cardiomyocytic expression of
NFAT3
317 leads to hypertrophy.14 However,
it is not clear whether the phenotype was as severe as in the
calcineurin A(1
398) transgenic animals, and NFATs are known to play
a role in cardiac development.127 More details of the
NFAT3
317 model would be of interest.
| General Comments and Future Directions |
|---|
|
|
|---|
398) might
perturb excitation-contraction coupling, indirectly leading to cardiac
hypertrophy and heart failure. The effects of calcineurin
A(1
398) on Ca2+ transients and
contractility in transiently transfected myocytes or in
myocytes from the calcineurin A(1
398) transgenic animal would be of
interest. Calcineurin and the immunophilins also interact with
signaling systems that have not been discussed here. These include the
transforming growth factor ß receptor (reviewed in Reference 178178 ) and
the protein kinase A anchoring proteins, which are involved in
targeting protein kinase A to specific cellular locations (reviewed in
Reference 179179 ). Given the importance of protein kinase A in regulating
myocardial contractility through modulation of L-type
Ca2+ channel activity (reviewed in Reference 44 ),
this is another potential point of interaction between calcineurin and
Ca2+ handling. It is unlikely that a single signaling pathway is responsible for the overall hypertrophic response. Interaction of the calcineurin pathway with other signaling pathways, such as the MAPK pathways, should be examined. Intuitively, in the absence of more complex regulation, these 2 pathways would appear to be in opposition, 1 (MAPKs) promoting phosphorylation and the other (calcineurin) promoting dephosphorylation. Examination of MAPK involvement in the regulation of the transactivating activity of transcription factors that associate with NFAT would be worthwhile, and in this regard, GATA4 contains 1 strong MAPK recognition sequence at residues 102 to 105 (Pro-Val-Ser-Pro), as well as several (Ser/Thr)Pro sequences.106 With these thoughts in mind, I suggest that the involvement of calcineurin in myocardial hypertrophy has not been unambiguously established and that there is life after calcineurin for those of us working in this area.
Note Added in Proof
Transgenic mice cardiospecifically expressing constitutively
activated G
q develop cardiac hypertrophy, then dilated
cardiomyopathy and heart failure.202 The effects of CsA in
this model were equivocal. It did not diminish hypertrophy when heart
weight was expressed relative to body weight, but did so when heart
weight was expressed relative to tibial length. There was also an
indication that CsA prevented some (but not all) of the changes in gene
expression associated with hypertrophy in this model.
Received October 28, 1998; accepted January 25, 1999.
| References |
|---|
|
|
|---|
2.
Eichhorn E, Bristow MR. Medical therapy can improve
the biological properties of the chronically failing heart: a new era
in the treatment of heart failure. Circulation. 1996;94:22852296.
3. Wagoner LE, Walsh RA. The cellular pathophysiology of progression to heart failure. Curr Opin Cardiol. 1996;11:237244.[Medline] [Order article via Infotrieve]
4.
Richard S, Leclercq F, Lemaire S, Piot C, Nargeot J.
Ca2+ currents in compensated
hypertrophy and heart failure. Cardiovasc Res. 1998;37:300311.
5.
Wickenden AD, Kaprielian R, Kassiri Z, Tsoporis JN,
Tsushima R, Fishman GI, Backx PH. The role of action potential
elongation and altered intracellular calcium handling in the
pathogenesis of heart failure. Cardiovasc Res. 1998;37:312323.
6.
Anversa P, Kajstura J. Ventricular
myocytes are not terminally differentiated cells in the adult mammalian
heart. Circ Res. 1998;83:114.
7.
Soonpaa MH, Field LJ. Survey of studies
examining cardiomyocyte DNA synthesis. Circ Res. 1998;83:1526.
8.
Krämer BK, Nishida M, Kelly RA, Smith TW.
Endothelins: myocardial actions of a new class of cytokines.
Circulation. 1992;85:350356.
9. Sugden PH, Bogoyevitch MA. Endothelin-1-dependent signaling pathways in the myocardium. Trends Cardiovasc Med. 1996;6:8794.
10.
Sei CA, Glembotski CC. Calcium dependence of
phenylephrine-, endothelin-, and potassium
chloride-stimulated atrial natriuretic factor secretion
from long term primary neonatal rat atrial cardiocytes.
J Biol Chem. 1990;265:71667172.
11.
Sadoshima J, Izumo S. Signal transduction pathways of
angiotensin II-induced c-fos gene expression in
cardiac myocytes in vitro. Circ Res. 1993;73:424438.
12.
Sadoshima J, Qiu Z, Morgan JP, Izumo S.
Angiotensin II and other hypertrophic stimuli mediated by G
protein-coupled receptors activate tyrosine kinase,
mitogen-activated protein kinase, and 90-kD S6 kinase in
cardiac myocytes: the critical role of
Ca2+-dependent signaling. Circ Res. 1995;76:115.
13.
Olson EN, Molkentin JD. Prevention of cardiac
hypertrophy by calcineurin inhibition: hope or hype?
Circ Res. 1999;84:623632.
14. Molkentin JD, Lu J-R, Antos C, Markham B, Richardson J, Robbins J, Grant SR, Olson EN. A calcineurin-dependent transcriptional pathway for cardiac hypertrophy. Cell. 1998;93:215228.[Medline] [Order article via Infotrieve]
15.
Barinaga M. Signaling pathways may lead to better
heart-failure therapies. Science. 1998;280:383.
16. Izumo S, Aoki H. Calcineurin: the missing link in cardiac hypertrophy. Nat Med. 1998;4:661662.[Medline] [Order article via Infotrieve]
17. Chien KR, Knowlton KU, Zhu H, Chien S. Regulation of cardiac gene expression during myocardial growth and hypertrophy: molecular studies of an adaptive physiologic response. FASEB J. 1991;5:30373046.[Abstract]
18. Komuro I, Yazaki Y. Control of cardiac gene expression by mechanical stress. Annu Rev Physiol. 1993;55:5575.[Medline] [Order article via Infotrieve]
19. Sugden PH, Clerk A. Cellular mechanisms of cardiac hypertrophy. J Mol Med. 1998;76:725746.[Medline] [Order article via Infotrieve]
20.
Hanford DS, Thuerauf DJ, Murray SF, Glembotski CC.
Brain natriuretic peptide is induced by
1-adrenergic agonists as a primary response
gene in cultured rat cardiac myocytes. J Biol Chem. 1994;269:2622726233.
21.
Hasenfuss G. Alterations of calcium-regulatory
proteins in heart failure. Cardiovasc Res. 1998;37:279289.
22.
Mably JD, Liew CC. Factors involved in cardiogenesis
and the regulation of cardiac-specific gene expression. Circ
Res. 1996;79:413.
23.
Wiesner RJ, Ehmke H, Faulhaber J, Zak R, Rüegg
JC. Dissociation of left ventricular
hypertrophy, ß-myosin heavy chain gene expression,
and myosin isoform switch in rats, after ascending aortic
stenosis. Circulation. 1997;95:12531259.
24.
Chien KR. Cardiac muscle diseases in genetically
engineered mice: evolution of molecular physiology. Am J
Physiol. 1995;269:H755H766.
25.
Becker KD, Gottshall KR, Chien KR. Strategies for
studying cardiovascular phenotypes in
genetically manipulated mice. Hypertension. 1996;27:495501.
26.
MacLellan WR, Schneider MD. Success in failure:
modeling cardiac decompensation in transgenic mice.
Circulation. 1998;97:14331435.
27.
Ng WA, Grupp IL, Subramaniam A, Robbins J.
Cardiac myosin heavy chain mRNA expression and myocardial function in
the mouse heart. Circ Res. 1991;68:17421750.
28. He H, Giordano FJ, Hilal-Dandan R, Choi DJ, Rockman HA, McDonough PM, Bluhm WF, Meyer M, Sayen MR, Swanson E, Dillmann WH. Overexpression of the rat sarcoplasmic reticulum Ca2+ ATPase gene in hearts of transgenic mice accelerates calcium transients and cardiac relaxation. J Clin Invest. 1997;100:380389.[Medline] [Order article via Infotrieve]
29. Jones LR, Suzuki YJ, Wang W, Kobayashi YM, Ramesh V, Franzini-Armstrong C, Cleeman L, Morad M. Regulation of Ca2+ signaling in transgenic mouse cardiac myocytes overexpressing calsequestrin. J Clin Invest. 1998;101:13851393.[Medline] [Order article via Infotrieve]
30.
Gottshall KR, Hunter JJ, Tanaka N, Dalton N, Becker
KD, Ross J Jr, Chien KR. Ras-dependent pathways induce obstructive
hypertrophy in echo-selected transgenic mice. Proc
Natl Acad Sci U S A. 1997;94:47104715.
31. Sugden PH, Clerk A. Regulation of the ERK subgroup of MAP kinase cascades through G protein-coupled receptors. Cell Signal. 1997;9:337351.[Medline] [Order article via Infotrieve]
32.
Sugden PH, Clerk A. "Stress-responsive"
mitogen-activated protein kinases in the
myocardium. Circ Res. 1998;83:345352.
33.
Sheng Z, Knowlton K, Chen J, Hoshijama M, Brown JH,
Chien KR. Cardiotrophin 1 (CT-1) inhibition of cardiac myocyte
apoptosis via a mitogen-activated protein
kinase-dependent pathway: divergence from downstream CT-1 signals for
myocardial cell hypertrophy. J Biol Chem. 1997;272:57835791.
34.
Kodama H, Fukuda K, Pan J, Makino S, Sano M,
Takahashi T, Hori S, Ogawa S. Biphasic activation of the JAK/STAT
pathway by angiotensin II in rat
cardiomyocytes. Circ Res. 1998;82:244250.
35. McWhinney CD, Dostal D, Baker K. Angiotensin II activates Stat5 through Jak2 kinase in cardiac myocytes. J Mol Cell Cardiol. 1998;30:751761.[Medline] [Order article via Infotrieve]
36.
Ramirez MT, Zhao XL, Schulman H, Brown JH. The
nuclear
B isoform of
Ca2+/calmodulin-dependent protein
kinase II regulates atrial natriuretic factor gene
expression in ventricular myocytes. J Biol
Chem. 1997;272:3120331208.
37. Aoki H, Sadoshima J, Izumo S. The critical role of myosin light chain phosphorylation in cardiac myofibrillogenesis in cardiac hypertrophy in vitro. Circulation. 1998;98(suppl I):I-839. Abstract.
38.
Alvarez E, Northwood IC, Gonzalez FA, Latour DA, Seth
A, Abate C, Curran T, Davis RJ. Pro-Leu-Ser/Thr-Pro is a consensus
primary sequence for substrate protein phosphorylation.
J Biol Chem. 1991;266:1527715285.
39.
Davis RJ. The mitogen-activated protein
kinase signal transduction pathway. J Biol Chem. 1993;268:1455314556.
40. Madhani HD, Fink GR. The riddle of MAP kinase signaling specificity. Trends Genet. 1998;14:151155.[Medline] [Order article via Infotrieve]
41.
Vojtek AB, Der CJ. Increasing complexity of the
Ras signaling pathway. J Biol Chem. 1998;273:1992519928.
42.
Mackay DJG, Hall A. Rho GTPases. J Biol
Chem. 1998;273:2068520688.
43.
Clerk A, Bogoyevitch MA, Andersson MB, Sugden PH.
Differential activation of protein kinase C isoforms by endothelin-1
and phenylephrine, and subsequent stimulation of p42 and
p44 mitogen-activated protein kinases in
ventricular myocytes cultured from neonatal rat hearts.
J Biol Chem. 1994;269:3284832857.
44.
Pucéat M, Hilal-Dandan R, Strulovici B, Brunton
LL, Brown JH. Differential regulation of protein kinase C isoforms in
isolated neonatal and adult rat cardiomyocytes.
J Biol Chem. 1994;269:1693816944.
45.
Rybin VO, Steinberg SF. Protein kinase C isoform
expression and regulation in the developing heart. Circ Res. 1994;74:299309.
46.
Clerk A, Bogoyevitch MA, Fuller SJ, Lazou A, Parker
PJ, Sugden PH. Expression of protein kinase C isoforms during cardiac
ventricular development. Am J Physiol. 1995;269:H1087H1097.
47.
Henrich CJ, Simpson PC. Differential acute and
chronic response of protein kinase C in cultured neonatal rat heart
myocytes to
1 adrenergic and phorbol
ester stimulation. J Mol Cell Cardiol. 1988;20:10811085.[Medline]
[Order article via Infotrieve]
48. Dunnmon PM, Iwaki K, Henderson SA, Sen A, Chien KR. Phorbol esters induce immediate-early genes and activate cardiac gene transcription in neonatal rat myocardial cells. J Mol Cell Cardiol. 1990;22:901910.[Medline] [Order article via Infotrieve]
49.
Bogoyevitch MA, Marshall CJ, Sugden PH. Hypertrophic
agonists stimulate the activities of the protein kinases c-Raf and
A-Raf in cultured ventricular myocytes. J Biol
Chem. 1995;270:2630326310.
50.
Bogoyevitch MA, Glennon PE, Andersson MB, Clerk A,
Lazou A, Marshall CJ, Parker PJ, Sugden PH. Endothelin-1 and fibroblast
growth factors stimulate the mitogen-activated protein kinase
signaling cascade in cardiac myocytes: the potential role of the
cascade in the integration of two signaling pathways leading to myocyte
hypertrophy. J Biol Chem. 1994;269:11101119.
51. Bogoyevitch MA, Glennon PE, Sugden PH. Endothelin-1, phorbol esters and phenylephrine stimulate MAP kinase activities in ventricular cardiomyocytes. FEBS Lett. 1993;317:271275.[Medline] [Order article via Infotrieve]
52. Marais R, Light Y, Paterson HF, Marshall CJ. Ras recruits Raf-1 to the plasma membrane for activation by tyrosine phosphorylation. EMBO J. 1995;14:31363145.[Medline] [Order article via Infotrieve]
53.
Marais R, Light Y, Paterson HF, Mason CS, Marshall
CJ. Differential regulation of Raf-1, A-Raf, and B-Raf by oncogenic Ras
and tyrosine kinases. J Biol Chem. 1997;272:43784383.
54. Cohen P. The search for physiological substrates of MAP and SAP kinases in mammalian cells. Trends Cell Biol. 1997;7:353361.
55.
Bogoyevitch MA, Ketterman AJ, Sugden PH. Cellular
stresses differentially activate the c-Jun N-terminal protein
kinases and the extracellular signal-regulated protein kinases in
cultured ventricular myocytes. J Biol Chem. 1995;270:2971029717.
56. Clerk A, Michael A, Sugden PH. Stimulation of multiple mitogen-activated protein kinase sub-families by oxidative stress and phosphorylation of the small heat shock protein, HSP25/27, in neonatal ventricular myocytes. Biochem J. 1998;333:581589.
57.
Clerk A, Michael A, Sugden PH. The G protein coupled
receptor agonists, endothelin-1 and phenylephrine,
stimulate p38 mitogen-activated protein kinase pathway in
neonatal rat ventricular myocytes. J Cell
Biol. 1998;142:523535.
58.
Johnson NL, Gardner AM, Diener KM, Lange-Carter CA,
Gleavy J, Jarpe MB, Minden A, Karin M, Zon LI, Johnson GL. Signal
transduction pathways regulated by
mitogen-activated/extracellular response kinase kinase kinase
induce cell death. J Biol Chem. 1996;271:32293237.
59.
Zechner D, Craig R, Hanford DS, McDonough PM,
Sabbadini RA, Glembotski CC. MKK6 activates myocardial cell
NF-
B and inhibits apoptosis in a p38
mitogen-activated protein kinase-dependent manner. J
Biol Chem. 1998;273:82328239.
60.
Wang Y, Huang S, Sah VP, Ross J, Brown JH, Han J,
Chien KR. Cardiac muscle cell hypertrophy and
apoptosis induced by distinct members of the p38
mitogen-activated protein kinase family. J Biol
Chem. 1998;273:21612168.
61.
Nemoto S, Sheng Z, Lin A. Opposing effects of Jun
kinase and p38 mitogen-activated protein kinases on
cardiomyocyte hypertrophy. Mol Cell
Biol. 1998;18:35183526.
62.
Adams JW, Migita DS, Yu MK, Young R, Hellickson MS,
Domingo JD, Lee PH, Bui JS, Henderson SA. Prostaglandin
F2
stimulates hypertrophic growth of cultured
neonatal rat ventricular myocytes. J Biol
Chem. 1996;271:11791186.
63.
Lai J, Jin H, Yang R, Winer J, Li W, Yen R, King KL,
Zeigler F, Ko A, Cheng J, Bunting S, Paoni NF.
Prostaglandin F2
induces cardiac
myocyte hypertrophy in vitro and cardiac growth in vivo.
Am J Physiol. 1996;271:H2197H2208.
64.
Adams JW, Sah VP, Henderson SA, Brown JH. Tyrosine
kinase and c-Jun NH2-terminal kinase mediate
hypertrophic responses to prostaglandin
F2
in cultured neonatal rat
ventricular myocytes. Circ Res. 1998;83:167178.
65.
Glennon PE, Kaddoura S, Sale EM, Sale GJ, Fuller SJ,
Sugden PH. Depletion of mitogen-activated protein kinase using
an antisense oligodeoxynucleotide approach down-regulates
the phenylephrine-induced hypertrophic response in rat
cardiac myocytes. Circ Res. 1996;78:954961.
66. Thorburn J, Carlson M, Mansour SJ, Chien KR, Ahn NG, Thorburn A. Inhibition of a signaling pathway in cardiac muscle cells by active mitogen-activated protein kinase kinase. Mol Biol Cell. 1995;6:14791490.[Abstract]
67. Fuller SJ, Davies EL, Gillespie-Brown J, Sun H, Tonks NK. Mitogen-activated protein kinase phosphatase 1 inhibits the stimulation of gene expression by hypertrophic agonists in cardiac myocytes. Biochem J. 1997;323:313319.
68.
Post GR, Goldstein D, Thuerauf DJ, Glembotski CC,
Brown JH. Dissociation of p42 and p44 mitogen-activated protein
kinase activation from receptor-induced hypertrophy in
neonatal rat ventricular myocytes. J Biol
Chem. 1996;271:84528457.
69.
Hines WA, Thorburn A. Ras and Rho are required for
G
q-induced hypertrophic gene expression in neonatal rat cardiac
myocytes. J Mol Cell Cardiol. 1998;30:485494.[Medline]
[Order article via Infotrieve]
70.
Zechner D, Thuerauf DJ, Hanford DS, McDonough PM,
Glembotski CC. A role for the p38 mitogen-activated protein
kinase pathway in myocardial cell growth, sarcomeric organization, and
cardiac-specific gene expression. J Cell Biol. 1997;139:115127.
71. Clerk A, Sugden PH. Phosphorylation of c-Jun and ATF2 in ventricular myocytes by endothelin and phenylephrine. Biochem Soc Trans. 1997;25:222S.[Medline] [Order article via Infotrieve]
72.
Thuerauf DJ, Arnold ND, Zechner D, Hanford DS,
DeMartin KM, McDonough PM, Prywes R, Glembotski CC.
p38-mitogen-activated protein kinase mediates the
transcriptional induction of the atrial natriuretic factor
gene through a serum response element: a potential role for the
transcription factor ATF6. J Biol Chem. 1998;273:2063620643.
73. Clerk A, Gillespie-Brown J, Fuller SJ, Sugden PH. Stimulation of phosphatidylinositol hydrolysis, protein kinase C translocation, and mitogen-activated protein kinase activation by bradykinin in rat ventricular myocytes: dissociation from the hypertrophic response. Biochem J. 1996;317:109118.
74.
LaMorte VJ, Thorburn J, Absher D, Spiegel A, Brown
JH, Chien KR, Feramisco JR, Knowlton KU. Gq- and
ras-dependent pathways mediate hypertrophy of neonatal rat
ventricular myocytes following
1-adrenergic stimulation. J Biol
Chem. 1994;269:1349013496.
75.
Kariya K, Karns LR, Simpson PC. Expression of a
constitutively activated mutant of the ß-isozyme of
protein kinase C in cardiac myocytes stimulates the promoter of the
ß-myosin heavy chain isogene. J Biol Chem. 1991;266:1002310026.
76.
Shubeita HE, Martinson EA, van Bilsen M, Chien KR,
Brown JH. Transcriptional activation of the cardiac myosin light chain
2 and atrial natriuretic factor genes by protein kinase C
in neonatal rat ventricular myocytes. Proc Natl Acad
Sci U S A. 1992;89:13051309.
77. Decock JB, Gillespie-Brown J, Parker PJ, Sugden PH, Fuller SJ. Classical, novel and atypical isoforms of PKC stimulate ANF- and TRE/AP-1-regulated-promoter activity in ventricular cardiomyocytes. FEBS Lett. 1994;356:275278.[Medline] [Order article via Infotrieve]
78.
Thorburn A, Thorburn J, Chen S-Y, Powers S, Shubeita
HE, Feramisco JR, Chien KR. HRas-dependent pathways can
activate morphological and genetic markers of cardiac muscle
cell hypertrophy. J Biol Chem. 1993;268:22442249.
79.
Fuller SJ, Gillespie-Brown J, Sugden PH. Oncogenic
raf, src, and ras stimulate a
hypertrophic pattern of gene expression and increase cell size in
neonatal rat ventricular myocytes. J Biol
Chem. 1998;273:1814618152.
80.
Kova
i
B, Ili
D, Damsky CH,
Gardner DG. c-Src plays a role in endothelin-dependent
hypertrophy of the cardiac myocyte. J Biol
Chem. 1998;273:3518535193.
81.
Akhter SA, Luttrell LM, Rockman HA, Iaccarino G,
Lefkowitz RJ, Koch WJ. Targeting the receptor-Gq
interface to inhibit in vivo pressure overload hypertrophy.
Science. 1998;280:574577.
82.
Hunter JJ, Tanaka N, Rockman HA, Ross J Jr, Chien KR.
Ventricular expression of a MLC-2-v-ras fusion gene induces
cardiac hypertrophy and selective diastolic
dysfunction in transgenic mice. J Biol Chem. 1995;270:2317323178.
83. Bowman JC, Steinberg SF, Jiang T, Geenan DL, Fishman GI, Buttrick PM. Expression of protein kinase C ß in the heart causes hypertrophy in adult mice and sudden death in neonates. J Clin Invest. 1997;100:21892195.[Medline] [Order article via Infotrieve]
84.
D'Angelo DD, Sakata Y, Lorenz JN, Boivin GP, Walsh
RA, Liggett SB, Dorn GW, II. Transgenic G
q overexpression
induces cardiac contractile failure in mice. Proc Natl Acad Sci
U S A. 1997;94:81218126.
85.
Wakasaki H, Koya D, Schoen FJ, Jirousek MR, Ways DK,
Hoit BD, Walsh RA, King GL. Targeted overexpression of protein kinase
C ß2 isoform in myocardium causes
cardiomyopathy. Proc Natl Acad Sci
U S A. 1997;94:93209325.
86.
Sakata Y, Hoit BD, Liggett SB, Walsh RA, Dorn GW II.
Decompensation of pressure-overload hypertrophy in
G
q-overexpressing mice. Circulation. 1998;97:14881495.
87. Amano M, Fukata Y, Kaibuchi K. Regulation of cytoskeleton and cell adhesions by the small GTPase Rho and its targets. Trends Cardiovasc Med. 1998;8:162168.
88. Mellor H, Parker PJ. The extended PKC superfamily. Biochem J. 1998;332:281292.
89.
Sah VP, Hoshijima M, Chien KR, Brown JH. Rho is
required for G
q and
1-adrenergic receptor signaling in
cardiomyocytes: dissociation of Ras and Rho pathways.
J Biol Chem. 1996;271:3118531190.
90. Thorburn J, Xu S, Thorburn A. MAP kinase and Rho-dependent signals interact to regulate gene expression but not actin morphology in cardiac muscle cells. EMBO J. 1997;16:18881900.[Medline] [Order article via Infotrieve]
91.
Aoki H, Izumo S, Sadoshima J. Angiotensin
II activates RhoA in cardiac myocytes: a critical role of RhoA
in angiotensin IIinduced premyofibril formation.
Circ Res. 1998;82:666676.
92.
Hoshijima M, Sah VP, Wang Y, Chien KR, Brown JH. The
low molecular weight GTPase Rho regulates myofibril formation and
organization in neonatal rat ventricular myocytes:
involvement of Rho kinase. J Biol Chem. 1998;273:77257730.
93. Guerini D. Calcineurin: not just a simple protein phosphatase. Biochem Biophys Res Commun. 1997;235:271275.[Medline] [Order article via Infotrieve]
94.
Klee CB, Ren H, Wang X. Regulation of the
calmodulin-stimulated protein phosphatase, calcineurin.
J Biol Chem. 1998;273:1336713370.
95. O'Keefe SJ, Tamura J, Kincaid RL, Tocci MJ, O'Neill EA. FK-506- and CsA-sensitive activation of the interleukin-2 promoter by calcineurin. Nature. 1992;357:692694.[Medline] [Order article via Infotrieve]
96. Rao A. NF-ATp: a transcription factor required for the co-ordinate induction of several cytokine genes. Immunol Today. 1994;15:274281.[Medline] [Order article via Infotrieve]
97. Rao A, Luo C, Hogan PG. Transcription factors of the NFAT family: regulation and function. Annu Rev Immunol. 1997;15:707747.[Medline] [Order article via Infotrieve]
98. Shibasaki F, Price ER, Milan D, McKeon F. Role of kinases and the phosphatase calcineurin in the nuclear shuttling of transcription factor NF-AT4. Nature. 1996;382:370373.[Medline] [Order article via Infotrieve]
99.
Boss V, Talpade DJ, Murphy TJ. Induction of
NFAT-mediated transcription by Gq-coupled
receptors in lymphoid and non-lymphoid cells. J Biol
Chem. 1996;271:1042910432.
100.
Boss V, Abbott KL, Wang X-F, Pavlath GK, Murphy TJ.
The cyclosporin A-sensitive nuclear factor of activated T cells
(NFAT) proteins are expressed in vascular smooth muscle cells:
differential localization of NFAT isoforms and induction of
NFAT-mediated transcription by phospholipase C-coupled cell surface
receptors. J Biol Chem. 1998;273:1966419671.
101.
Chow C-W, Rincón M, Cavanagh J, Dickens M, Davis
RJ. Nuclear accumulation of NFAT4 opposed by the JNK signal
transduction pathway. Science. 1997;278:16381641.
102. Zhu J, Shibasaki F, Price R, Guillemot JC, Yano T, Dotsch V, Wagner G, Ferrara P, McKeon F. Intramolecular masking of nuclear import signal on NF-AT4 by casein kinase I and MEKK1. Cell. 1998;93:851861.[Medline] [Order article via Infotrieve]
103.
Beals CR, Sheridan CR, Turck CW, Gardner P, Crabtree
GR. Nuclear export of NF-ATc enhanced by glycogen synthase kinase-3.
Science. 1997;275:19301933.
104. Klemm JD, Beals CR, Crabtree GR. Rapid targeting of nuclear protein to the cytoplasm. Curr Biol. 1997;7:638644.[Medline] [Order article via Infotrieve]
105.
Matsuda S, Moriguchi T, Koyasu S, Nishida E. T
lymphocyte activation signals for interleukin-2 production
involve activation of MKK6p38 and MKK7-SAPK/JNK signaling pathways
sensitive to cyclosporin. J Biol Chem. 1998;273:1237812382.
106.
Arceci RJ, King AA, Simon MC, Orkin SH, Wilson DB.
Mouse GATA-4: a retinoic acid-inducible GATA-binding transcription
factor expressed in endodermally derived tissues and heart. Mol
Cell Biol. 1993;13:22352246.
107. Molkentin JD, Olson EN. GATA4: a novel transcriptional regulator of cardiac hypertrophy? Circulation. 1997;96:38333835.
108.
Grépin C, Dagnino L, Robitaille L, Haberstroh L,
Antakly T, Nemer M. A hormone-encoding gene identifies a pathway for
cardiac but not skeletal muscle gene transcription. Mol Cell
Biol. 1994;14:31153129.
109.
Hasegawa K, Lee SJ, Jobe SM, Markham BE, Kitsis RN.
cis-acting sequences that mediate induction of ß-myosin
heavy chain expression during left ventricular
hypertrophy due to aortic constriction.
Circulation. 1997;96:39433953.
110.
Lee Y, Shioi T, Kasahar H, Jobe SM, Wiese RJ, Markham
BE, Izumo S. The cardiac tissue-restricted homeobox protein Csx/Nkx2.5
physically associates with the zinc finger protein GATA4 and
cooperatively activates atrial natriuretic factor
gene expression. Mol Cell Biol. 1998;18:31203129.
111.
Komuro I, Izumo S. Csx: a murine
homeobox-containing gene specifically expressed in the developing
heart. Proc Natl Acad Sci U S A. 1993;90:81458149.
112. Lints TJ, Parsons LM, Hartley L, Lyons I, Harvey RP. Nkx-2.5: a novel murine homeobox gene expressed in early heart progenitor cells and their myogenic descendants. Development. 1993;119:419431.[Abstract]
113.
Boluyt MO, Zheng J-S, Younes A, Long X, O'Neill L,
Silverman H, Lakatta EG, Crow MT. Rapamycin inhibits
1-adrenergic receptor-stimulated cardiac
myocyte hypertrophy but not activation of
hypertrophy-associated genes: evidence for involvement of
p70 S6 kinase. Circ Res. 1997;81:176186.
114.
Kohmoto O, Ikenouchi H, Hirata Y, Momomura S, Serizawa
T, Barry WH. Variable effects of endothelin-1 on
[Ca2+]i transients,
pHi, and contraction in ventricular
myocytes. Am J Physiol. 1993;265:H793H800.
115.
Ikenouchi H, Barry WH, Bridge JHB, Weinberg EO,
Apstein CS, Lorell BH. Effects of angiotensin II on
intracellular Ca2+ and pH in isolated beating
rabbit hearts and in myocytes loaded with the indicator indo-1.
J Physiol (Cambr). 1994;480:203215.
116. Ito N, Kagaya Y, Weinberg EO, Barry WH, Lorell BH. Endothelin and angiotensin II stimulation of Na+/H+ exchanger is impaired in cardiac hypertrophy. J Clin Invest. 1997;99:123135.
117.
Terzic A, Pucéat M, Vassort G, Vogel SM.
Cardiac
1-adrenoceptors: an overview.
Pharmacol Rev. 1993;45:147175.[Medline]
[Order article via Infotrieve]
118. Pucéat M, Vassort G. Neurohumoral modulation of intracellular pH in the heart. Cardiovasc Res. 1995;29:178183.[Medline] [Order article via Infotrieve]
119.
Orlowski J, Grinstein S.
Na+/H+ exchangers of
mammalian cells. J Biol Chem. 1997;272:2237322376.
120. Kretsinger RH. Calcium-binding proteins. Annu Rev Biochem. 1976;45:239266.[Medline] [Order article via Infotrieve]
121. Kretsinger RH. Structure and evolution of calcium-modulated proteins. CRC Crit Rev Biochem. 1980;8:119174.[Medline] [Order article via Infotrieve]
122. Vaughan-Jones RD, Lederer WJ, Eisner DA. Ca2+ ions can affect intracellular pH in mammalian cardiac muscle. Nature. 1983;301:522524.[Medline] [Order article via Infotrieve]
123. Sugden PH, Fuller SJ. Correlations between cardiac protein synthesis rates, intracellular pH and the concentrations of creatine metabolites. Biochem J. 1991;273:339346.
124. Dolmetsch RE, Lewis RS, Goodnow CC, Healy JI. Differential activation of transcription factors induced by Ca2+ response amplitude and duration. Nature. 1997;386:855858.[Medline] [Order article via Infotrieve]
125. Dolmetsch RE, Xu K, Lewis RS. Calcium oscillations increase the efficiency and specificity of gene transcription. Nature. 1998;392:933936.[Medline] [Order article via Infotrieve]
126.
Gruver CL, DeMayo F, Goldstein MA, Means AR. Targeted
developmental overexpression of calmodulin induces
proliferative and hypertrophic growth of cardiomyocytes in
transgenic mice. Endocrinology. 1993;133:376388.
127. de la Pompa JL, Timmerman LA, Takimoto H, Yoshida H, Elia AJ, Samper E, Potter J, Wakeham A, Marengere L, Langille BL, Crabtree GR, Mak TW. Role of the NF-ATc transcription factor in the morphogenesis of cardiac valves and septum. Nature. 1998;392:182186.[Medline] [Order article via Infotrieve]
128. Henning SW, Cantrell DA. GTPases in antigen receptor signalling. Curr Opin Immunol. 1998;10:322329.[Medline] [Order article via Infotrieve]
129. Chen L, Glover JNM, Hogan PG, Rao S, Harrison SC. Structure of the DNA-binding domains from NFAT, Fos and Jun bound specifically to DNA. Nature. 1998;392:4248.[Medline] [Order article via Infotrieve]
130.
Karin M. The regulation of AP-1 activity by
mitogen-activated protein kinases. J Biol Chem. 1995;270:1648316486.
131. Minden A, Karin M. Regulation and function of the JNK subgroup of MAP kinases. Biochim Biophys Acta. 1997;1333:F85F104.[Medline] [Order article via Infotrieve]
132. Reif K, Cantrell DA. Networking Rho family GTPase in lymphocytes. Immunity. 1998;8:395401.[Medline] [Order article via Infotrieve]
133. Livingstone C, Patel G, Jones N. ATF-2 contains a phosphorylation-dependent transcriptional activation domain. EMBO J. 1995;14:17851797.[Medline] [Order article via Infotrieve]
134. Van Dam H, Wilhelm D, Herr I, Steffen A, Herrlich P, Angel P. ATF-2 is preferentially activated by stress-activated protein kinases to mediate c-jun induction in response to genotoxic agents. EMBO J. 1995;14:17981811.[Medline] [Order article via Infotrieve]
135.
Whitmarsh AJ, Shore P, Sharrocks AD, Davis RJ.
Integration of MAP kinase signal transduction pathways at the serum
response element. Science. 1995;269:403407.
136. Bogoyevitch MA, Andersson MB, Gillespie-Brown J, Clerk A, Glennon PE, Fuller SJ, Sugden PH. Adrenergic receptor stimulation of the mitogen-activated protein kinase cascade and cardiac hypertrophy. Biochem J. 1996;314:115121.
137.
McDonough PM, Hanford DS, Sprenkle AB, Mellon NR,
Glembotski CC. Collaborative roles for c-Jun N-terminal kinase, c-Jun,
serum response factor, and Sp1 in calcium-regulated myocardial gene
expression. J Biol Chem. 1997;272:2404624053.
138.
Ho PD, Zechner DK, He H, Dillmann WH, Glembotski CC,
McDonough PM. The Raf-MEK-ERK cascade represents a common
pathway for the alteration of intracellular calcium by Ras and protein
kinase C in cardiac myocytes. J Biol Chem. 1998;273:2173021735.
139.
Sussman MA, Lim HW, Gude N, Taigen T, Olson EN,
Robbins J, Colbert MC, Gualberto A, Wieczorek DF, Molkentin JD.
Prevention of cardiac hypertrophy in mice by calcineurin
inhibition. Science. 1998;281:16901693.
140. Luo X, Shyu K-G, Gualberto A, Walsh K. Calcineurin inhibitors and cardiac hypertrophy. Nat Med. 1998;4:10921093.[Medline] [Order article via Infotrieve]
141. Müller JG, Nemoto S, Laser M, Carabello BA, Menick DR. Calcineurin inhibition and cardiac hypertrophy. Science. 1998;282:1007. Available at: http://www.sciencemag.org/cgi/content/full/282/5391/1007a. Accessed November 13, 1998.
142. Molkentin JD. Calcineurin inhibition and cardiac hypertrophy: response. Science. 1998;282:1007. Available at: http://www.sciencemag.org/cgi/content/full/282/5391/1007a. Accessed November 13, 1998.
143.
Aperia A, Ibarra F, Svensson LB, Klee C, Greengard P.
Calcineurin mediates
-adrenergic stimulation of
Na+,K+-ATPase activity in
renal tubule cells. Proc Natl Acad Sci U S A. 1992;89:73947397.
144. Radermacher J, Meiners M, Bramlage C, Kliem V, Behrend M, Schlitt HJ, Pichlmayr R, Koch KM, Brunkhorst R. Pronounced renal vasoconstriction and systemic hypertension in renal transplant patients treated with cyclosporin versus FK-506. Transpl Int. 1998;11:310.[Medline] [Order article via Infotrieve]
145. Rowan RA, Billingham ME. Pathologic changes in the long-term transplanted heart: a morphometric study of myocardial hypertrophy, vascularity, and fibrosis. Hum Pathol. 1990;21:767772.[Medline] [Order article via Infotrieve]
146. Lipkin GW, Tucker B, Giles M, Raine AE. Ambulatory blood pressure and left ventricular mass in cyclosporin- and non-cyclosporin-treated renal transplant patients. J Hypertens. 1993;11:439442.[Medline] [Order article via Infotrieve]
147. Ventura HO, Lavie CJ, Messerli FH, Smart FW, Stapleton DD, Ochsner JL. Cardiovascular adaptation to cyclosporine-induced hypertension. J Hum Hypertens. 1994;8:233237.[Medline] [Order article via Infotrieve]
148. Globits S, De Marco T, Schwitter J, Sakuma H, O'Sullivan M, Rifkin C, Keith F, Chatterjee K, Parmley WW, Higgins CB. Assessment of early left ventricular remodeling in orthotopic heart transplant recipients with cine magnetic resonance imaging: potential mechanisms. J Heart Lung Transplant. 1997;16:504510.[Medline] [Order article via Infotrieve]
149.
Chin ER, Olson EN, Richardson JA, Yang Q, Humphries C,
Shelton JM, Wu H, Zhu W, Bassel-Duby R, Williams RS. A
calcineurin-dependent transcriptional pathway controls skeletal muscle
fiber type. Genes Dev. 1998;12:24992509.
150.
Sabbah HN, Hansen-Smith F, Sharov VG, Kono T, Lesch M,
Gengo PJ, Steffen RP, Levine TB, Goldstein S. Decreased proportion of
type I myofibers in skeletal muscle of dogs with chronic heart failure.
Circulation. 1993;87:17291737.
151.
Harrington D, Coats AJS. Skeletal muscle abnormalities
and evidence for their role in symptom generation in chronic heart
failure. Eur Heart J. 1997;18:18651872.
152. Stern MD. Theory of excitation-contraction coupling in cardiac muscle. Biophys J. 1992;63:497517.[Medline] [Order article via Infotrieve]
153.
Gwathmey JK, Morgan JP. Altered calcium handling in
pressure-overload hypertrophy in the ferret. Circ
Res. 1985;57:836843.
154.
Gwathmey JK, Copelas L, McKinnin R, Schoen FJ, Feldman
MD, Grossman W, Morgan JP. Altered intracellular calcium handling in
myocardium from patients with end-stage heart failure.
Circ Res. 1987;61:7076.
155. Santella L, Carafoli E. Calcium signaling in the cell nucleus. FASEB J. 1997;11:10911109.[Abstract]
156.
Sato Y, Ferguson DG, Sako H, Dorn GW, II, Kadambi VJ,
Yatani A, Hoit BD, Walsh RA, Kranias EG. Cardiac-specific
overexpression of mouse cardiac calsequestrin is associated with
depressed cardiovascular function and
hypertrophy in transgenic mice. J Biol
Chem. 1998;273:2847028477.
157.
Luo W, Grupp IL, Harrer J, Ponniah S, Grupp G, Duffy
JJ, Doetschman T, Kranias EG. Targeted ablation of the phospholamban
gene is associated with markedly enhanced cardiac
contractility and loss of ß agonist stimulation.
Circ Res. 1994;75:401409.
158. Valdivia HH. Modulation of intracellular Ca2+ levels in the heart by sorcin and FKBP12, two accessory proteins of ryanodine receptors. Trends Pharmacol Sci. 1998;19:479482.[Medline] [Order article via Infotrieve]
159. Shou W, Aghdasi B, Armstrong DL, Guo Q, Bao S, Charng MJ, Mathews LM, Schneider MD, Hamilton SL, Matzuk MM. Cardiac defects and altered ryanodine receptor function in mice lacking FKBP12. Nature. 1998;391:489492.[Medline] [Order article via Infotrieve]
160.
Perez PJ, Ramos-Franco J, Fill M, Mignery GA.
Identification and functional reconstitution of the type 2 inositol
1,4,5-trisphosphate receptor from ventricular cardiac
myocytes. J Biol Chem. 1997;272:2396123969.
161.
Cameron AM, Nucifora NC Jr, Fung ET, Livingston DJ,
Aldape RA, Ross CA, Snyder SH. FKBP12 binds the inositol
1,4,5-trisphosphate receptor at leucine-proline (14001401) and
anchors calcineurin to this FK-506-like domain. J Biol
Chem. 1997;272:2758227588.
162. Halestrap AP, Connern CP, Griffiths EJ, Kerr PM. Cyclosporin A binding to mitochondrial cyclophilin inhibits the permeability transition pore and protects hearts from ischaemia/reperfusion injury. Mol Cell Biochem. 1997;174:167172.[Medline] [Order article via Infotrieve]
163. Bernardi P. The permeability transition pore: control points of a cyclosporin A-sensitive mitochondrial channel involved in cell death. Biochim Biophys Acta. 1998;1275:59.
164. Halestrap AP, Kerr PM, Javadov S, Woodfield KY. Elucidating the molecular mechanism of the permeability transition pore and its role in reperfusion injury of the heart. Biochim Biophys Acta. 1998;1366:7994.[Medline] [Order article via Infotrieve]
165.
Halestrap AP, Woodfield KY, Connern CP. Oxidative
stress, thiol reagents, and membrane potential modulate the
mitochondrial permeability transition by affecting
nucleotide binding to adenine nucleotide
translocase. J Biol Chem. 1997;272:33463354.
166. Griffiths EJ, Halestrap AP. Protection by cyclosporin A of ischemia/reperfusion-induced damage in isolated rat hearts. J Mol Cell Cardiol. 1993;25:14611469.[Medline] [Order article via Infotrieve]
167. Massoudy P, Zahler S, Kupatt C, Reder E, Becker BF, Gerlach E. Cardioprotection by cyclosporine A in experimental ischemia and reperfusion: evidence for a nitric oxide-dependent mechanism mediated by endothelin. J Mol Cell Cardiol. 1997;29:535544.[Medline] [Order article via Infotrieve]
168.
Weinbrenner C, Liu GS, Downey JM, Cohen MV.
Cyclosporine A limits myocardial infarct size even when
administered after onset of ischemia. Cardiovasc
Res. 1998;38:676684.
169.
MacLellan WR, Schneider MD. Death by design.
Circ Res. 1997;81:137144.
170.
Haunstetter A, Izumo S. Apoptosis, basic
mechanisms and implications for cardiovascular disease.
Circ Res. 1998;82:11111129.
171.
Shibasaki F, McKeon F. Calcineurin functions in
Ca2+-activated cell death in mammalian
cells. J Cell Biol. 1995;131:735743.
172. Shibasaki F, Kondo E, Akagi T, McKeon F. Suppression of signalling through transcription factor NF-AT by interactions between calcineurin and Bcl-2. Nature. 1997;386:728731.[Medline] [Order article via Infotrieve]
173. Genestier L, Dearden-Badet MT, Bonnefoy-Berard N, Lizard G, Revillard JP. Cyclosporin A and FK-506 inhibit activation-induced cell death in the murine WEHI-231 B cell line. Cell Immunol. 1994;155:283291.[Medline] [Order article via Infotrieve]
174. Reed JC. Double identity for proteins of the Bcl-2 family. Nature. 1997;387:773776.[Medline] [Order article via Infotrieve]
175.
Narula J, Haider N, Virmani R, DiSalvo TG, Kolodgie
FD, Hajjar RJ, Schmidt U, Semigran MJ, Dec GW, Khaw BA.
Apoptosis in myocytes in end-stage heart failure. N
Engl J Med. 1996;335:11821189.
176.
Olivetti G, Abbi R, Quaini F, Kajstura J, Cheng W,
Nitahara JA, Quaini E, Di Loreto C, Beltrami CA, Krajewski S, Reed JC,
Anversa P. Apoptosis in the failing human heart. N
Engl J Med. 1997;336:11311141.
177.
Walter DH, Haendele J, Galle J, Zeiher AM, Dimmeler S.
Cyclosporin A inhibits apoptosis of human
endothelial cells by preventing release of cytochrome c
from mitochondria. Circulation. 1998;98:11531157.
178. Massagué J. TGF-ß signal transduction. Annu Rev Biochem. 1998;67:753791.[Medline] [Order article via Infotrieve]
179.
Dell'Acqua ML, Scott JD. Protein kinase A anchoring.
J Biol Chem. 1997;272:1288112884.
180.
Shubeita HE, McDonough PM, Harris AN, Knowlton KU,
Glembotski CC, Brown JH, Chien KR. Endothelin induction of inositol
phospholipid hydrolysis, sarcomere assembly, and cardiac gene
expression in ventricular myocytes: a paracrine mechanism
for myocardial cell hypertrophy. J Biol
Chem. 1990;265:2055520562.
181.
Ito H, Hirata Y, Hiroe M, Tsujino M, Adachi S,
Takamoto T, Nitta M, Taniguchi K, Marumo F. Endothelin-1 induces
hypertrophy with enhanced expression of muscle-specific
genes in cultured neonatal rat cardiomyocytes. Circ
Res. 1991;69:209215.
182.
Sadoshima J, Izumo S. Molecular characterization of
angiotensin II-induced hypertrophy of cardiac
myocytes and hyperplasia of cardiac fibroblasts: critical role of the
AT1 receptor subtype. Circ Res. 1993;73:413423.
183.
Simpson P. Stimulation of hypertrophy of
cultured neonatal rat heart cells through an
1-adrenergic receptor and induction of beating
through an
1- and
ß1-adrenergic receptor interaction: evidence
for independent regulation of growth and beating. Circ Res. 1985;56:884894.
184.
Knowlton KU, Baracchini E, Ross RS, Harris AN,
Henderson SA, Evans SM, Glembotski CC, Chien KR. Co-regulation of the
atrial natriuretic factor and cardiac myosin light chain-2
genes during
-adrenergic stimulation of neonatal rat
ventricular cells: identification of cis
sequences within an embryonic and a constitutive contractile protein
gene which mediate inducible expression. J Biol Chem. 1991;266:77597768.
185. Parker TG, Packer SE, Schneider MD. Peptide growth factors can provoke "fetal" contractile protein gene expression in rat cardiac myocytes. J Clin Invest. 1990;85:507514.
186.
Ito H, Hiroe M, Hirata Y, Tsujino M, Adachi S,
Shichiri M, Koike A, Nogami A, Marumo F. Insulin-like growth factor-1
induces hypertrophy with enhanced expression of
muscle-specific genes in cultured rat cardiomyocytes.
Circulation. 1993;87:17151721.
187.
Pennica D, King KL, Shaw KJ, Luis E, Rullamas J, Luoh
S-M, Darbonne WC, Knutzon DS, Yen R, Chien KR, Baker JB, Wood WI.
Expression cloning of cardiotrophin 1, a cytokine that induces
cardiac myocyte hypertrophy. Proc Natl Acad Sci
U S A. 1995;92:11421146.
188.
Komuro I, Kaida T, Shibazaki Y, Kurabayashi M, Katoh
Y, Hoh E, Takaku F, Yazaki Y. Stretching cardiac myocytes stimulates
protooncogene expression. J Biol Chem. 1990;265:35953598.
189.
Komuro I, Katoh Y, Kaida T, Shibazaki Y, Kurabayashi
M, Hoh E, Takaku F, Yazaki Y. Mechanical loading stimulates cell
hypertrophy and specific gene expression in cultured rat
cardiac myocytes: possible role of protein kinase C activation.
J Biol Chem. 1991;266:12651268.
190.
Sadoshima J, Jahn L, Takahashi T, Kulik TJ, Izumo S.
Molecular characterization of stretch-induced adaptation of cultured
cardiac cells: an in vitro model of load induced cardiac
hypertrophy. J Biol Chem. 1992;267:1055110560.
191. Sadoshima J, Izumo S. Mechanical stretch rapidly activates multiple signal transduction pathways in cardiac myocytes: potential involvement of an autocrine/paracrine mechanism. EMBO J. 1993;12:16811692.[Medline] [Order article via Infotrieve]
192.
Yamazaki T, Komuro I, Kudoh S, Zou Y, Shiojima I,
Hiroi Y, Mizuno T, Maemura K, Kurihara H, Aikawa R, Takano H, Yazaki Y.
Endothelin-1 is involved in mechanical stress-induced
cardiomyocyte hypertrophy. J Biol
Chem. 1996;271:32213228.
193.
Liang F, Gardner DG. Autocrine/paracrine determinants
of strain-activated brain natriuretic peptide gene
expression in cultured cardiac myocytes. J Biol Chem. 1998;273:1461214619.
194. Sadoshima J, Xu Y, Slayter HS, Izumo S. Autocrine release of angiotensin II mediates stretch-induced hypertrophy of cardiac myocytes in vitro. Cell. 1993;75:977984.[Medline] [Order article via Infotrieve]
195. Clark WA, Decker ML, Behnke-Barclay M, Janes DM, Decker RS. Cell contact as an independent factor modulating cardiac myocyte hypertrophy and survival in long-term primary culture. J Mol Cell Cardiol. 1998;30:139155.[Medline] [Order article via Infotrieve]
196.
Thorburn J, Frost JA, Thorburn A.
Mitogen-activated protein kinases mediate changes in gene
expression, but not cytoskeletal organization associated with cardiac
muscle hypertrophy. J Cell Biol. 1994;126:15651572.
197.
Thorburn J, McMahon M, Thorburn A. Raf-1 kinase
activity is necessary and sufficient for gene expression changes but
not sufficient for cellular morphology changes associated with cardiac
myocyte hypertrophy. J Biol Chem. 1994;269:3058030586.
198.
Gillespie-Brown J, Fuller SJ, Bogoyevitch MA, Cowley
S, Sugden PH. The mitogen-activated protein kinase kinase MEK1
stimulates a pattern of gene expression typical of the hypertrophic
phenotype in rat ventricular
cardiomyocytes. J Biol Chem. 1995;270:2809228096.
199.
Ramirez MT, Sah VP, Zhao X-L, Hunter JJ, Chien KR,
Brown JH. The MEKK-JNK pathway is stimulated by
1-adrenergic receptor and ras activation and
is associated with in vitro and in vivo cardiac
hypertrophy. J Biol Chem. 1997;272:1405714061.
200. Choukroun G, Hajjar R, Kyriakis JM, Bonventre JV, Rosenzweig A, Force T. Role of the stress-activated protein kinases in endothelin-induced cardiomyocyte hypertrophy. J Clin Invest. 1998;102:13111320.[Medline] [Order article via Infotrieve]
201.
Wang Y, Su B, Sah VP, Brown JH, Han J, Chien KR.
Cardiac hypertrophy induced by mitogen-activated
protein kinase kinase 7, a specific activator for c-Jun
NH2-terminal kinase in ventricular
muscle cells. J Biol Chem. 1998;273:54235426.
202.
Mende U, Kagen A, Cohen J, Aramburu J, Schoen FJ, Neer
EJ. Transient cardiac expression of constitutively activated
G
q leads to cardiac hypertrophy and dilated
cardiomyopathy by calcineurin-dependent and independent pathways.
Proc Natl Acad Sci U S A. 1998;95:1389313898.
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||||
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||||
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||||
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||||
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||||
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||||
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||||
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||||
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||||
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||||
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||||
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||||
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||||
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||||
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||||
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||||
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||||
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||||
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||||
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||||
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||||
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||||
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||||
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||||
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