Published online before print June 21, 2001, doi: 10.1161/hh1301.092688
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© 2001 American Heart Association, Inc.
Integrative Physiology |
Expression of R120G–
B-Crystallin Causes Aberrant Desmin and B-Crystallin Aggregation and Cardiomyopathy in Mice
From the Division of Molecular Cardiovascular Biology (X.W., H.O., R.K., T.H., J.R.), Children’s Hospital Research Foundation, Cincinnati, Ohio; South Dakota Health Research Foundation–Cardiovascular Research Institute (A.M.G.), Sioux Falls, SD; and Department of Molecular and Cellular Physiology (M.N., J.L.), University of Cincinnati Medical Center, Cincinnati, Ohio.
Correspondence to Jeffrey Robbins, Division of Molecular Cardiovascular Biology, Children’s Hospital Research Foundation, 3333 Burnet Ave, Cincinnati, OH 45229. E-mail jeff.robbins{at}chmcc.org
Abstract
Abstract—Upregulation
of 
B-crystallin (CryAB), a small heat shock protein, is associated
with a variety of diseases, including the desmin-related myopathies.
CryAB, which binds to both desmin and cytoplasmic actin, may
participate as a chaperone in intermediate filament formation and
maintenance, but the physiological
consequences of CryAB upregulation are unknown. A mutation in CryAB,
R120G, has been linked to a familial desminopathy. However, it is
unclear whether the mutation is directly causative. We created multiple
transgenic mouse lines that overexpressed either murine wild-type CryAB
or the R120G mutation in cardiomyocytes. Overexpression of
wild-type CryAB was relatively benign, with no increases in mortality
and no induction of desmin-related cardiomyopathy
even in a line in which CryAB mRNA expression was increased 
104-fold
and the protein level increased by 11-fold. In contrast, lines
expressing the R120G mutation were compromised, with a high-expressing
line exhibiting 100% mortality by early adulthood. Modest expression
levels resulted in a phenotype that was strikingly similar to
that observed for the desmin-related
cardiomyopathies. The desmin filaments in the
cardiomyocytes were overtly affected, myofibril alignment
was significantly impaired, and a hypertrophic response occurred at
both the molecular and cellular levels. The data show that the R120G
mutation causes a desminopathy, is dominant negative, and results in
cardiac hypertrophy.
Key Words: transgenic • heart disease • mouse • cardiac • genetics
The small heat
shock–related protein B-crystallin (CryAB) was originally
discovered and classified as a lens
protein.1 CryAB is also found
in nonlenticular tissues and is abundant in cardiac and skeletal
muscle.2 3 CryAB
binds both desmin and cytoplasmic actin and possesses molecular
chaperone function in
vitro.4 5 6
When a cell is subjected to stress, CryAB transits from the cytosol
onto the cytoskeleton.7
Phosphorylation by mitogen-activated protein
kinase, p38, and other kinases may regulate this translocation and
presumably its chaperone
function.8 9 The
upregulation of the gene and subsequent accumulation of CryAB occurs in
a number of cardiac disorders including familial hypertrophic
cardiomyopathy and
desminopathy,10 11 12
as well as degenerative neural pathologies such as Alexander and
Alzheimer
diseases.2 13
However, the pathophysiological significance, if
any, of CryAB protein upregulation in muscle remains
obscure.
A missense mutation (R120G) of CryAB has recently been linked to familial desmin-related myopathy (DRM), a disease that is characterized by intrasarcoplasmic accumulation of desmin.14 Restrictive, hypertrophic, and dilated cardiomyopathies have all been observed in the desminopathies and often result in death.12 15 Overexpression of R120G-CryAB in a muscle cell line caused formation of electron-dense aggregates containing CryAB in the center and desmin at the periphery.14 However, there is no direct in vivo evidence, outside of linkage analysis, proving that the missense mutation of CryAB causes DRM. Furthermore, if the mutation is directly causative, it remains to be explored how it leads to disease presentation.
To approach these issues, we generated multiple stable transgenic (TG) mouse lines that express different levels of either the wild-type (WT) or mutant CryAB proteins specifically in the heart. Whereas overexpression of WT CryAB protein was benign, expression of even very modest levels of R120G-CryAB protein led to aberrant desmin and CryAB aggregation, disruption of the desmin network, perturbation of myofibril alignment, and compromised muscle function.
Materials and Methods
An expanded Materials and Methods section is available online at http://www.circresaha.org.
Results
TG Mouse Lines
Both human genetic and in vitro biochemical data
indicate that the missense mutation (R120G) of CryAB acts in a
dominant-negative
fashion.14 16
Therefore, we chose to use a TG approach in an attempt to show direct
causality of the mutation in causing cardiovascular
disease and to create an animal model suitable for longitudinal
analyses of the pathogenic processes. To control for the
possibility that alterations in the overall stoichiometries of either
the CryAB transcript or protein pools might lead to a
phenotype, WT murine CryAB was also used to generate TG lines
in parallel with the R120G-CryAB construct (Figure 1
online, available
in the data supplement at http://www.circresaha.org). Three TG lines
(lines 11, 13, and 41) were made using WT-CryAB cDNA, whereas three TG
lines (lines 25, 134, and 708) expressed the R120G-CryAB transgene.
Germline transmission was confirmed, and normal mendelian ratios were
observed, indicating that no embryonic lethality occurred with either
construct with those particular lines. Genomic Southern blotting
(Figure 1A) showed that the transgene copy numbers of
the WT-CryAB lines 11, 13, and 41 were 22, 120, and 60, respectively.
Those of R120G lines 708, 25, and 134 were 1, 1, and 3, respectively.
CryAB transcript and protein levels determined
(Figures 1B and 1C). Consistent with the copy numbers,
all of the WT-CryAB TG lines showed higher CryAB mRNA and protein
levels as compared with the mutant lines
(Figures 1B through 1D). Increases in soluble CryAB protein
levels in the WT-CryAB TG lines accounted for essentially all of the
increase in protein. In contrast, the R120G lines show significant
increases in the insoluble, and presumably aggregated, fraction
(Figure 1D). We have now carried the WT-CryAB lines for 16
months. To date, there is no increase in mortality for the WT-CryAB TG
mice relative to nontransgenic (NTG) littermates. However, line 134
R120G-CryAB TG mice, which express the transgene at lower levels than
even those of line 11 (WT-CryAB), died at 5 to 7 months of age
(Figure 2). On dissection, the hearts were grossly enlarged
and dilated. Atrial thrombosis and sometimes calcification were
evident. Both pulmonary and hepatic congestion, pleural
effusion, and/or ascites, as well as subcutaneous edema, were observed
in the autopsies, a pathology consistent with death by
congestive heart failure. Line 708, which expresses R120G, but at lower
levels, also developed a similar phenotype but only after 12 to
16 months (data not shown). Line 25, which also contained a single copy
of the transgene, has not been studied in detail, although the
cardiomyocytes do show aggregates similar to those seen in
lines 134 and 708. Line 11 (WT-CryAB) and lines 708 and 134
(R120G-CryAB) were chosen for detailed characterization, as line 11 is
the WT-CryAB line of which the TG copy number and protein expression
level are closest to the mutant line.
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R120G-CryAB Causes Aberrant Desmin and CryAB
Aggregation
The hallmark of DRM is the presence of aberrant desmin
aggregates in myocytes of the affected muscle. These aggregates display
a unique morphology at the ultrastructural
level.15 We recently created
and characterized a TG mouse model of DRM, in which the disease is
caused by TG overexpression of a desmin cDNA that carries a mutation
that causes human disease.17
Because CryAB associates with desmin, we wished to determine whether
the R120G mutation resulted in a pathological outcome similar to DRM.
If the R120G mutation is sufficient and causative for DRM, expression
of the mutant protein in vivo should result in aggregate formation. We
used light microscopy, immunofluorescence confocal
microscopy, transmission electron microscopy, and immunoelectron
microscopy to characterize potential aberrant desmin aggregation in
12-week-old TG hearts. Virtually every myocyte in the line 134 R120G
CryAB TG hearts displayed eosinophilic aggregates in paraffin sections
that were stained with Gomori’s modified trichrome
(Figure 3). Although not as readily apparent in the
trichrome-stained sections, myocytes in the lower-expressing R120G
lines showed a similar morphology in that aggregates, which stained
intensely for CryAB, could be detected (Figure 2
online). Line 11, the
WT overexpressor, appeared normal
(Figure 3). The number and size of aggregates increased as
the R120G animals aged but could not be detected in the
WT-overexpressing lines at any age tested (data not shown).
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The distribution and organization of both desmin and CryAB
were investigated using immunofluorescence confocal
microscopy. Immunostaining for desmin in cardiac
myocytes showed that the desmin networks were well preserved in the
WT-CryAB TG heart and the staining pattern was not different from that
in NTG hearts
(Figures 4a and 4b). The normal desmin network was, however,
disrupted in the R120G-CryAB TG hearts. The striated pattern was
absent, especially in the central parts of the cell; aberrant
aggregates of desmin were obvious
(Figure 4c). The immunolabeling in cardiac myocytes also
demonstrated that CryAB distribution in WT-CryAB TG hearts was normal.
The transverse striated pattern is apparent in both NTG and WT-CryAB
cardiomyocytes
(Figures 4d and 4e), although the increased CryAB level in the
WT-CryAB TG cells resulted in a more homogenous staining background
with higher fluorescent intensity
(Figure 4e). Abnormal CryAB-positive aggregates were
prominent in the R120G TG myocytes
(Figure 4f and online Figure 2B, available at
http://www.circresaha.org) but were not present in either the
WT-CryAB TG or the NTG cells. Double-immunostaining for
desmin and CryAB was subsequently performed to decipher the
relationship between the desmin and CryAB aggregates. Although some
regions of the aberrant CryAB aggregates were desmin positive as
evidenced by the yellow color (overlay), the desmin aggregates (red)
were, for the most part, distributed outside of the CryAB (green)
aggregates
(Figure 4i).
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As noted above, the hallmark of DRM is the appearance of
electron-dense, granular aggregates in the cytoplasm of the affected
cells.18 These structures
were abundant in the R120G cardiomyocytes. Two populations
of electron-dense aggregates, named type I and II, were present in
the intermyofibrillar space
(Figure 5). Type I aggregates
(Figure 5c, asterisk) had a relatively low electron density
and occupied a large portion of the central part of the
cardiomyocyte. They were substantially larger and more
regular in shape than type II. They had clear boundaries but were not
enclosed in a membrane. In comparison with type II aggregates, they
contained finer granules. Type II aggregates
(Figure 5c, arrow) were relatively small but more numerous.
They were irregular in shape and surrounded by numerous fine filaments.
Morphologically, type II aggregates resembled the desmin aggregates
observed in TG animals that expressed the mutant desmin
protein.17 Some of the type
II aggregates appear to be associated with the nuclear envelope and
others with the Z-band
(Figure 5c). No direct physical association between the two
aggregate types was apparent
(Figure 5c), although occasionally we noted that type II
aggregates were trapped in type I aggregates (data not shown).
Immunoelectron microscopy analyses confirmed that type I
aggregates were CryAB positive
(Figure 6c) with only a few scattered grains resulting from
immunogold labeling with the desmin antibody
(Figure 7b). Type II aggregates were CryAB and desmin
positive
(Figures 6 and 7). A number of desmin-positive filaments
outside of the type II aggregates were also observed, but no
filamentous structure was associated with type I aggregates
(Figure 7b). Ultrastructural analyses also showed
that the alignment of adjacent myofibrils at the Z-band was perturbed
in the R120G-CryAB TG hearts
(Figure 5c). Generally in these animals, Z-band thickness was
increased and its normal uniformity lost
(Figures 5 through 7). The pathologies were essentially
identical between the left and right ventricles.
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Expression of the CryAB Mutation Causes Cardiac
Hypertrophy
Common outcomes of DRM are skeletal muscle atrophy and
cardiac hypertrophy and, as expression of the mutant
protein was restricted to the heart, we wished to determine whether the
R120G mice recapitulated this aspect of the human disease. At the
molecular level, activation of fetal genetic programs is common during
the early stages of hypertrophy, with upregulation of
atrial natriuretic factor and ß-myosin and downregulation
of -myosin, phospholamban, and the sarcoplasm reticulum calcium
pump. Transcript levels were measured at 1, 3, and 6 months of age as
the R120G pathology developed (Figure 3 online, available at
http://www.circresaha.org). The relative amounts of these transcripts
as well as those of desmin and total CryAB showed a pattern
consistent with the morphological disarray apparent in the
confocal and transmission electron microscopy analyses. That
is, expression of R120G-CryAB but not overexpression of WT-CryAB
triggered a hypertrophic response at the molecular level in the heart.
By 3 months, hypertrophy was apparent at the gross level as
well, with significant increases in the ventricular
weight/tibial length ratios (Figure 4A online). Hypertrophy
continued to develop and was even more pronounced at 6
months.
To determine whether the cardiomyocytes
themselves were larger, the cell volume, profile area, and length, as
well as the transverse sectional area (TSA), were measured at 3 and 6
months (Figure 4 online). In both the left and right ventricles,
cardiomyocyte size progressively increased
(P<0.01) in the R120G-CryAB TG
mice as compared with the NTG and WT-CryAB TG controls. At 3 months,
the increase in cell size was due to increases in the TSA. By 6 months,
both the cell length and TSA were larger, indicating that concentric
hypertrophy at the cellular level occurs in both ventricles
at 3 months and ventricular chamber dilatation occurs later
on as the heart begins to fail. This is consistent with the
clinical progression observed in many cardiovascular
diseases, in which a compensatory hypertrophy is observed
early, but later on decompensated heart failure presents. No
abnormalities were observed in the cohort that overexpressed the WT
protein.
R120G-CryAB Leads to Cardiac
Dysfunction
Cardiac function in patients with DRM is often
significantly compromised. As the disease progresses, the heart
dilates, systolic function becomes compromised, and heart
failure occurs. Considering the effects of R120G-CryAB expression on
the cellular structure and organization, and the resultant
hypertrophy, we wished to measure the impact of R120G-CryAB
or WT-CryAB TG expression on cardiac function at 3 months of age. In
the early stages of compensatory hypertrophy, contractile
function is often maintained or even increased, whereas deficits in
relaxation begin to occur.19
To divorce the system from endogenous ß-adrenergic
stimulation and determine whether any functional deficits
presented at this stage, an isolated work-performing heart
preparation20 was used
(Figure 8A). Contractile function, as measured using the left
ventricular pressure waveform in the isolated
work-performing heart, showed that +dP/dt was higher in the R120G-CryAB
TG hearts than in the NTG and WT-CryAB TG controls
(P<0.005). Relaxation, as
measured by the first derivative of left ventricular
pressure (-dP/dt), was significantly lower than in either control
cohort (P<0.005).
|
0.05, #P
By 6 months, the animals’ presentation was
consistent with severe heart failure and, rather than the
working heart, in vivo
hemodynamics17 21
were used so that the neurohumoral axis, which helps to maintain
cardiac function, could be taken into account. In vivo
hemodynamics showed that baseline absolute values of
both dP/dtmax and
dP/dtmin were significantly decreased relative
to the NTG and WT-CryAB TG controls. Even when stimulated via
catecholamines, the hearts were unable to maintain normal
contractility and an overt response to ß-agonist
stimulation via dobutamine infusion was substantially
blunted
(Figures 8B and 8C). Determination of tau
(Figure 8D), the monoexponential time
constant of relaxation, showed that the deficits in relaxation were
relatively load independent. The data show that cardiac function is
significantly compromised.
Discussion
Cardiac and skeletal muscles contain the highest CryAB levels among the nonlenticular tissues. Upregulation of CryAB occurs in a number of cardiac disorders, including familial hypertrophic cardiomyopathy and DRM, but the functional consequences are unknown. Linkage of R120G-CryAB to familial DRM suggests that normal CryAB function, which presumably involves chaperone activity, is crucial for desmin filament formation and/or function. Interestingly, the mutant CryAB protein appears to be relatively resistant to degradation as compared with normal CryAB. As the TG mice age, total CryAB protein in the mutant CryAB hearts progressively increases, whereas CryAB protein levels stay relatively constant in the WT-CryAB TG heart despite much higher transcript levels (data not shown). The relationship between CryAB, desmin, and DRM pathogenesis remains obscure. The data presented in this study show that upregulation of normal CryAB is not, by itself, detrimental to the heart. However, in the intact animal, the R120G mutation results in both abnormal CryAB aggregation and aberrant desmin aggregation. The sequelae accurately recapitulate the progression of cardiovascular disease as the heart first attempts to compensate for the structural insult by hypertrophying but eventually transits into a decompensated, dilated state with heart failure as the final outcome.
No discernible phenotype presented in the WT-CryAB TG mice, supporting the conclusion that simple alterations in CryAB stoichiometry are not responsible for the phenotype. Oligomerization is required for CryAB to exert its molecular chaperone function,16 22 and this is consistent with the R120G-missense mutation of CryAB being dominant negative. The genetics of the R120G mutation indicate an autosomal dominant inherited pattern in the human disease,14 and in vitro analyses of R120G-CryAB polymers, or a mixture of R120G:WT-CryAB protein, result in altered morphology and compromised molecular chaperone function.16 22 The TG mice offer possible insights into the functional deficits that result. The type I and II aggregates in the R120G mice are intriguing. The two types of aggregates are distinguished both by their morphology and by their protein composition. Type I aggregates are CryAB positive and contain only traces of desmin, whereas type II aggregates are both desmin and CryAB positive and are similar to the characteristic desmin aggregates found in DRM hearts carrying desmin mutations. It is well established that WT CryAB binds to desmin and desmin filaments, especially when cells are stressed.4 23 24 We hypothesize that the relative paucity of desmin in the R120G-CryAB–loaded type I aggregates is due to the inability of the mutant CryAB to productively interact with desmin. The data also indicate that desmin aggregate formation in these mice is not due to a physical or biochemical interaction between desmin and the R120G mutant CryAB. Indeed, formation of the aberrant desmin aggregates may be caused by a loss of function of the mutant CryAB.
We observed significant differences in copy number and
expression levels for the WT versus R120G transgenes
(Figure 1). The explanation probably lies in the embryonic
lethality of embryos containing higher copy numbers of the R120G
transgene. In fact, an R120G-CryAB founder with 30 copies of the
transgene died at 8 weeks and so could not be bred. Another founder,
who was mosaic for the transgene, produced TG pups who all died from
congestive heart failure before 4 weeks. When analyzed, these
mice had 40 copies of the R120G transgene, and the histology (at 3
weeks) showed tremendous aggregate accumulation in the
cardiomyocytes (data not shown).
Previously we produced a mouse model of DRM by
cardiac-specific expression of a transgene containing a desmin mutation
that causes human disease.17
Those mice did not exhibit the severe morbidity and mortality that
present in the R120G animals. Similarly, desmin-null mice also
exhibit a less severe pattern of morbidity and
mortality.25 26 27
Thus, both loss-of-function and dominant-negative alleles of desmin
result in disease, but the pathology is markedly less severe than that
resulting from the R120G-CryAB mutation. R120G TG mice develop cardiac
hypertrophy that is concentric at an early stage (3 months)
but leads to dilation and failure by 5 to 7 months. All mice from line
134, which have only three copies of the transgene, die during this
period. Unfortunately, there is a lack of human data in terms of
mutant/WT protein expression with which we can compare the mouse data.
The earlier adulthood high mortality of line 134 relative to lines 708
and 25 is almost certainly due to the higher dosage. The higher level
of mutant protein expression gives rise to a more pronounced
phenotype at an earlier time. We have noted that line 708 TG
mice also tend to die prematurely, but this is apparent only in the
older adult population, and statistically significant data have not yet
been accumulated, although there are alterations at the
cardiomyocyte level (Figure 2 online, available at
http://www.circresaha.org). The desmin-null mice also die prematurely,
but a substantial percentage of the null cohort survives for up to a
year.25 26 The
desmin mutation–induced DRM TG cohorts live for at least 18
months.17 These observations
suggest that the cardiac dysfunction caused by R120G-CryAB must be due
to more than just a loss of desmin function and imply either additional
roles for CryAB that can impact on the general cytoskeletal
architecture or other, as-yet-undefined targets for CryAB
interaction(s).
In the young adults (3 months), systolic function is
actually increased as measured using the isolated working heart
preparation
(Figure 8A). Although this may appear to be somewhat
surprising, at this early stage, the R120G TG mice show concentric
hypertrophy (Figure 4 online). The hypertrophic
myocardium displayed an increased +dP/dt in response to
changes in preload, and we have observed similar +/-dP/dt profiles in
the early stage of concentric hypertrophy induced by
pressure overload. Occurrence of hypertrophy at this stage
might be due to functional deficit in diastole. Recently,
we have evaluated in vivo left ventricular function on
3-month-old mice. Similarly, baseline +dP/dtmax
of the R120G TG mice was unaffected (X. Wang and J. Robbins,
unpublished observations, 2001). Histological changes
at 3 months include primarily concentric hypertrophy with
minimal indications of the more advanced changes that accompany
failure. We observed the more severe histological
changes and increased mortality at 5 to 7 months and beyond and believe
the observed increases in +dP/dt at 3 months of age are
consistent with the early stages of a compensatory
hypertrophy. The primary performance effect of the
mutation is decreased diastolic function, which most likely
leads to initial compensation at 3 months and ultimate failure at 7
months and beyond.
In cardiomyocytes, desmin filaments link adjacent myofibrils to one another, to the cell membrane, and to the nuclear envelope.26 As other intermediate filaments do in other cells, the desmin filaments play an important role in maintaining the structural integrity of myocytes,25 and thus it is not surprising that alterations in a molecular chaperone, which functions in their transport, can have severe consequences. Previously, Vicart et al14 showed, via transfection of muscle cell cultures with the R120G mutant, that characteristic aggregates developed. Our data significantly extend these observations, showing that stable expression of a mutated chaperone in the heart can lead directly first to a compensated hypertrophy and eventually to heart failure. By combining a combination of biochemical and whole-animal approaches, it should be possible to define the role(s) of CryAB, both in normal cardiomyocyte function and in cardiovascular disease.
Acknowledgments
This work was supported by NIH Grants HL56370, HL41496, HL56620, HL52318, HL60546, and HL56620 (to J.R.) and HL62459 (to A.M.G.), and by the American Heart Association, Ohio Valley Affiliate (to X.W.).
Footnotes
Original received February 6, 2001; revision received May 8, 2001; accepted May 8, 2001.
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  H. Su and X. Wang The ubiquitin-proteasome system in cardiac proteinopathy: a quality control perspective Cardiovasc Res, September 16, 2009; (2009) cvp287v2. [Abstract] [Full Text] [PDF]
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O. Tsukamoto, T. Minamino, and M. Kitakaze Functional alterations of cardiac proteasomes under physiological and pathological conditions Cardiovasc Res, September 4, 2009; (2009) cvp282v2. [Abstract] [Full Text] [PDF]
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L. Carrier, S. Schlossarek, M. S. Willis, and T. Eschenhagen Ubiquitin-proteasome system and nonsense-mediated mRNA decay in hypertrophic cardiomyopathy Cardiovasc Res, August 10, 2009; (2009) cvp247v2. [Abstract] [Full Text] [PDF]
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 A. Maloyan, H. Osinska, J. Lammerding, R. T. Lee, O. H. Cingolani, D. A. Kass, J. N. Lorenz, and J. Robbins Biochemical and Mechanical Dysfunction in a Mouse Model of Desmin-Related Myopathy Circ. Res., April 24, 2009; 104(8): 1021 - 1028. [Abstract] [Full Text] [PDF]
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 S. B. Scruggs, A. C. Hinken, A. Thawornkaiwong, J. Robbins, L. A. Walker, P. P. de Tombe, D. L. Geenen, P. M. Buttrick, and R. J. Solaro Ablation of Ventricular Myosin Regulatory Light Chain Phosphorylation in Mice Causes Cardiac Dysfunction in Situ and Affects Neighboring Myofilament Protein Phosphorylation J. Biol. Chem., February 20, 2009; 284(8): 5097 - 5106. [Abstract] [Full Text] [PDF]
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M. S. Willis, J. C. Schisler, A. L. Portbury, and C. Patterson Build it up-Tear it down: protein quality control in the cardiac sarcomere Cardiovasc Res, February 15, 2009; 81(3): 439 - 448. [Abstract] [Full Text] [PDF]
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B. A. Rothermel and J. A. Hill Autophagy in Load-Induced Heart Disease Circ. Res., December 5, 2008; 103(12): 1363 - 1369. [Abstract] [Full Text] [PDF]
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A. R.K. Kumarapeli, H. Su, W. Huang, M. Tang, H. Zheng, K. M. Horak, M. Li, and X. Wang {alpha}B-Crystallin Suppresses Pressure Overload Cardiac Hypertrophy Circ. Res., December 5, 2008; 103(12): 1473 - 1482. [Abstract] [Full Text] [PDF]
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 P. Panagopoulou, C. H. Davos, D. J. Milner, E. Varela, J. Cameron, D. L. Mann, and Y. Capetanaki Desmin mediates TNF-{alpha}-induced aggregate formation and intercalated disk reorganization in heart failure J. Cell Biol., October 20, 2008; 181(5): 761 - 775. [Abstract] [Full Text] [PDF]
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 P. Tannous, H. Zhu, J. L. Johnstone, J. M. Shelton, N. S. Rajasekaran, I. J. Benjamin, L. Nguyen, R. D. Gerard, B. Levine, B. A. Rothermel, et al. Autophagy is an adaptive response in desmin-related cardiomyopathy PNAS, July 15, 2008; 105(28): 9745 - 9750. [Abstract] [Full Text] [PDF]
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 I. Pinz, J. Robbins, N. S. Rajasekaran, I. J. Benjamin, and J. S. Ingwall Unmasking different mechanical and energetic roles for the small heat shock proteins CryAB and HSPB2 using genetically modified mouse hearts FASEB J, January 1, 2008; 22(1): 84 - 92. [Abstract] [Full Text] [PDF]
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 J. Zhai, H. Lin, J.-P. Julien, and W. W. Schlaepfer Disruption of neurofilament network with aggregation of light neurofilament protein: a common pathway leading to motor neuron degeneration due to Charcot Marie Tooth disease-linked mutations in NFL and HSPB1 Hum. Mol. Genet., December 15, 2007; 16(24): 3103 - 3116. [Abstract] [Full Text] [PDF]
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 T. Bupha-Intr, J. W. Holmes, and P. M. L. Janssen Induction of hypertrophy in vitro by mechanical loading in adult rabbit myocardium Am J Physiol Heart Circ Physiol, December 1, 2007; 293(6): H3759 - H3767. [Abstract] [Full Text] [PDF]
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S. Simon, J.-M. Fontaine, J. L. Martin, X. Sun, A. D. Hoppe, M. J. Welsh, R. Benndorf, and P. Vicart Myopathy-associated {alpha}B-crystallin Mutants: ABNORMAL PHOSPHORYLATION, INTRACELLULAR LOCATION, AND INTERACTIONS WITH OTHER SMALL HEAT SHOCK PROTEINS J. Biol. Chem., November 23, 2007; 282(47): 34276 - 34287. [Abstract] [Full Text] [PDF]
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A. Maloyan, J. Gulick, C. G. Glabe, R. Kayed, and J. Robbins Exercise reverses preamyloid oligomer and prolongs survival in {alpha}B-crystallin-based desmin-related cardiomyopathy PNAS, April 3, 2007; 104(14): 5995 - 6000. [Abstract] [Full Text] [PDF]
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 C. Patterson, C. Ike, P. W. Willis IV, G. A. Stouffer, and M. S. Willis The Bitter End: The Ubiquitin-Proteasome System and Cardiac Dysfunction Circulation, March 20, 2007; 115(11): 1456 - 1463. [Abstract] [Full Text] [PDF]
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A. Sanbe, J. Yamauchi, Y. Miyamoto, Y. Fujiwara, M. Murabe, and A. Tanoue Interruption of CryAB-Amyloid Oligomer Formation by HSP22 J. Biol. Chem., January 5, 2007; 282(1): 555 - 563. [Abstract] [Full Text] [PDF]
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X. Wang and J. Robbins Heart Failure and Protein Quality Control Circ. Res., December 8, 2006; 99(12): 1315 - 1328. [Abstract] [Full Text] [PDF]
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D. Jeong, H. Cha, E. Kim, M. Kang, D. K. Yang, J. M. Kim, P. O. Yoon, J. G. Oh, O. Y. Bernecker, S. Sakata, et al. PICOT Inhibits Cardiac Hypertrophy and Enhances Ventricular Function and Cardiomyocyte Contractility Circ. Res., August 4, 2006; 99(3): 307 - 314. [Abstract] [Full Text] [PDF]
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S. M. Garvey, S. E. Miller, D. R. Claflin, J. A. Faulkner, and M. A. Hauser Transgenic mice expressing the myotilin T57I mutation unite the pathology associated with LGMD1A and MFM Hum. Mol. Genet., August 1, 2006; 15(15): 2348 - 2362. [Abstract] [Full Text] [PDF]
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O. Zolk, C. Schenke, and A. Sarikas The ubiquitin-proteasome system: Focus on the heart Cardiovasc Res, June 1, 2006; 70(3): 410 - 421. [Abstract] [Full Text] [PDF]
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H. A. Koteiche and H. S. Mchaourab Mechanism of a Hereditary Cataract Phenotype: MUTATIONS IN {alpha}A-CRYSTALLIN ACTIVATE SUBSTRATE BINDING J. Biol. Chem., May 19, 2006; 281(20): 14273 - 14279. [Abstract] [Full Text] [PDF]
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A. Maloyan, A. Sanbe, H. Osinska, M. Westfall, D. Robinson, K.-i. Imahashi, E. Murphy, and J. Robbins Mitochondrial Dysfunction and Apoptosis Underlie the Pathogenic Process in {alpha}-B-Crystallin Desmin-Related Cardiomyopathy Circulation, November 29, 2005; 112(22): 3451 - 3461. [Abstract] [Full Text] [PDF]
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Q. Chen, J.-B. Liu, K. M. Horak, H. Zheng, A. R.K. Kumarapeli, J. Li, F. Li, A. M. Gerdes, E. F. Wawrousek, and X. Wang Intrasarcoplasmic Amyloidosis Impairs Proteolytic Function of Proteasomes in Cardiomyocytes by Compromising Substrate Uptake Circ. Res., November 11, 2005; 97(10): 1018 - 1026. [Abstract] [Full Text] [PDF]
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J. den Engelsman, D. Gerrits, W. W. de Jong, J. Robbins, K. Kato, and W. C. Boelens Nuclear Import of {alpha}B-crystallin Is Phosphorylation-dependent and Hampered by Hyperphosphorylation of the Myopathy-related Mutant R120G J. Biol. Chem., November 4, 2005; 280(44): 37139 - 37148. [Abstract] [Full Text] [PDF]
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A. Sanbe, H. Osinska, C. Villa, J. Gulick, R. Klevitsky, C. G. Glabe, R. Kayed, and J. Robbins Reversal of amyloid-induced heart disease in desmin-related cardiomyopathy PNAS, September 20, 2005; 102(38): 13592 - 13597. [Abstract] [Full Text] [PDF]
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X. Dong, J. Liu, H. Zheng, J. W. Glasford, W. Huang, Q. H. Chen, N. R. Harden, F. Li, A. M. Gerdes, and X. Wang In situ dynamically monitoring the proteolytic function of the ubiquitin-proteasome system in cultured cardiac myocytes Am J Physiol Heart Circ Physiol, September 1, 2004; 287(3): H1417 - H1425. [Abstract] [Full Text] [PDF]
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A. Sanbe, H. Osinska, J. E. Saffitz, C. G. Glabe, R. Kayed, A. Maloyan, and J. Robbins Desmin-related cardiomyopathy in transgenic mice: A cardiac amyloidosis PNAS, July 6, 2004; 101(27): 10132 - 10136. [Abstract] [Full Text] [PDF]
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 M. Der Perng, S. F. Wen, P. van den IJssel, A. R. Prescott, and R. A. Quinlan Desmin Aggregate Formation by R120G {alpha}B-Crystallin Is Caused by Altered Filament Interactions and Is Dependent upon Network Status in Cells Mol. Biol. Cell, May 1, 2004; 15(5): 2335 - 2346. [Abstract] [Full Text] [PDF]
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 L. G. Goldfarb, P. Vicart, H. H. Goebel, and M. C. Dalakas Desmin myopathy Brain, April 1, 2004; 127(4): 723 - 734. [Abstract] [Full Text] [PDF]
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X. Wang, R. Klevitsky, W. Huang, J. Glasford, F. Li, and J. Robbins {alpha}B-Crystallin Modulates Protein Aggregation of Abnormal Desmin Circ. Res., November 14, 2003; 93(10): 998 - 1005. [Abstract] [Full Text] [PDF]
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A. T. Chavez Zobel, A. Loranger, N. Marceau, J. R. Theriault, H. Lambert, and J. Landry Distinct chaperone mechanisms can delay the formation of aggresomes by the myopathy-causing R120G {alpha}B-crystallin mutant Hum. Mol. Genet., July 1, 2003; 12(13): 1609 - 1620. [Abstract] [Full Text] [PDF]
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H. S. Hahn, M. G. Yussman, T. Toyokawa, Y. Marreez, T. J. Barrett, K. C. Hilty, H. Osinska, J. Robbins, and G. W. Dorn II Ischemic Protection and Myofibrillar Cardiomyopathy: Dose-Dependent Effects of In Vivo {delta}PKC Inhibition Circ. Res., October 18, 2002; 91(8): 741 - 748. [Abstract] [Full Text] [PDF]
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M. C. Kamradt, F. Chen, S. Sam, and V. L. Cryns The Small Heat Shock Protein alpha B-crystallin Negatively Regulates Apoptosis during Myogenic Differentiation by Inhibiting Caspase-3 Activation J. Biol. Chem., October 4, 2002; 277(41): 38731 - 38736. [Abstract] [Full Text] [PDF]
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A. J. Marian On Genetics of Dilated Cardiomyopathy and Transgenic Models : All Is Not Crystal Clear in Myopathic Hearts Circ. Res., July 6, 2001; 89(1): 3 - 5. [Full Text] [PDF]
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