© 2000 American Heart Association, Inc.
Editorials |
Cytokine Actions of Angiotensin II
From the Weis Center for Research, Pennsylvania State University College of Medicine, Danville, Pa.
Correspondence to Junichi Sadoshima, Weis Center for Research, Pennsylvania State University College of Medicine, Department of Molecular Cellular Physiology, 100 N Academy Ave, Danville, PA 17822. E-mail Jsadoshima{at}psghs.edu
Key Words: angiotensin II • nuclear factor-
B • cytokine • AT2
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Introduction |
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 Top Introduction Functional Roles of the...Signaling Mechanism of NF...Unresolved QuestionsReferences |
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During the last few years, there has been an exponential rise in understanding functions and signal transduction mechanisms for angiotensin II (Ang II) type 2 receptors (AT2s).1 2 These studies are particularly relevant in view of the pivotal role of upregulation of AT2 in mediating tissue remodeling in many cardiovascular diseases, including vascular injury, atherosclerosis, cardiac hypertrophy, myocardial infarction, and congestive heart failure.1 Furthermore, Ang II type 1 receptor (AT1) antagonists, commonly used for treatment of hypertension and congestive heart failure, increase plasma levels of Ang II and upregulate AT2 expression. Under these conditions, the increase in AT2 is unopposed by AT1.1 3 Thus, understanding the role of AT2 in cardiovascular remodeling as well as the consequences of AT2 stimulation or inhibition during medical therapy is clinically important. AT2s only partially share the signaling mechanisms with AT1s and, in fact, counteract the signaling mechanisms activated by AT1s2 (Figure
). This negative nature
of AT2 signaling has made the elucidation of its
function more difficult than that of AT1.
However, recent studies on the cardiovascular functions
of AT2 seem to have reached a consensus:
AT2s exert growth inhibitory effects
either by suppressing cell proliferation and
hypertrophy4 5 or by stimulating
apoptosis.1 2 6 These actions alone may not
explain the diverse cardiovascular phenomena attributed
to AT2, resulting in unanswered questions. Why
are AT2s abundant in growing fetal tissues? Why
are AT2s abundant in tissues undergoing
remodeling? Recently, an elegant genetic study has provided an answer
to some of these questions, showing that an important function of
AT2 in the fetal kidney is to stimulate
apoptosis. Targeted deletion of AT2
causes malformation of the kidney and urinary tract similar to that
observed in human CAKUT (congenital anomalies of the kidney and urinary
tract), a malformation caused by delayed apoptosis of
undifferentiated mesenchymal cells.7 Although execution of
apoptosis is certainly an important function of
AT2 during postnatal (pathological)
cardiovascular remodeling, some studies have pointed
out that AT2s may also be involved in
inflammatory and cell growth processes.8 9 10 11
|
In this issue of Circulation Research, Ruiz-Ortega et
al12 show that Ang II activates nuclear
factor-B (NF-B) through both AT1 and
AT2 in vascular smooth muscle cells. NF-B is a
ubiquitous transcription factor of particular importance in
inflammatory responses.13 Many stimuli relevant to
cardiovascular diseases, including proinflammatory
cytokines (interleukin [IL]-1ß and tumor necrosis
factor-
[TNF-]), signals elicited by ischemic stress
(nitric oxide [NO] and reactive oxygen species), and mechanical
forces, have been shown to activate NF-B. Activation of
NF-B leads to coordinated increases in the expression of many genes
whose products mediate inflammatory responses, including
cytokines, chemokines, and adhesion molecules.13
Although activation of NF-B by AT1 has been
demonstrated previously,14 the study by Ruiz-Ortega et
al12 is the first to show the linkage between
AT2 and NF-B and thus potentially clarifies
the mechanism of many presently unexplained
cardiovascular phenomena known to be mediated by
AT2.
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Functional Roles of the AT2/NF-B Pathway
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TopIntroductionFunctional Roles of the...Signaling Mechanism of NF...Unresolved QuestionsReferences |
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As Ruiz-Ortega et al12 point out, many inflammatory cytokines (TNF-
, IL-6, and IL-8), chemokines (monocyte
chemoattractant protein-1 [MCP-1]), cell adhesion molecules (vascular
cell adhesion molecule-1 and intercellular adhesion molecule-1), and
other molecules (tissue factor) relevant for
cardiovascular remodeling are regulated by NF-B.
Other important candidates regulated by the
AT2/NF-B pathway include inducible NO
synthase15 and
cyclooxygenase-2,16 which mediate NO
and prostaglandin and thromboxane
production, respectively, in inflammatory diseases. NO
synthesis and subsequent production of cGMP are stimulated by
AT2 in many organs.17 Induction of
cyclooxygenase-2 and activation of NF-B have
been observed in fibrotic scars in the myocardium of
failing human hearts.18 Remarkably,
AT2s in human hearts are predominantly localized
in fibroblasts present in the interstitial
region,1 suggesting that AT2 may be
responsible for progression of inflammation and
interstitial fibrosis during cardiac remodeling.
Stimulation of AT2 generally inhibits growth of
vascular smooth muscle cells4 and cardiac
myocytes,5 but, paradoxically, it may also be involved in
cell growth. For example, AT2 blockade inhibits
medial smooth muscle hypertrophy and fibrosis in the
thoracic aorta of Ang II–infused rats9 and spontaneously
hypertensive rats.10 Because these growth stimulatory
effects are seen only in vivo (and have not been reported in pure
smooth muscle cell cultures), upregulation of cytokines and
cell adhesion molecules by the AT2/NF-B
pathway, attraction of inflammatory cells, and additional amplification
of trophic (paracrine) factors in vivo may be responsible for these
AT2-mediated cell growth responses. Recently, a
preliminary study suggested that pressure overload–induced cardiac
hypertrophy is completely suppressed in mice with targeted
deletion of AT2.11 Although this
observation seems contradictory to known acute antihypertrophic effects
of AT2,5 the
AT2/NF-B pathway may chronically regulate
expression of cytokines, thereby preparing the trophic
environment for hypertrophy and remodeling. Alternatively,
stretch-induced secretion of Ang II and subsequent amplification of
inflammatory cytokines through the
AT2/NF-B pathway may mediate pressure
overload–induced cardiac hypertrophy. In fact,
macrophage infiltration has been demonstrated in the
myocardium subjected to mechanical overload.19
Expression of AT2 is upregulated by IL-1ß,
insulin, and insulin-like growth factor and downregulated by
glucocorticoids.20 All these stimuli exert directionally
similar effects on NF-B and AT2. This raises
the possibility that the NF-B site found in the
AT2 promoter may mediate transcription of
AT2. Products of genes that are regulated by
NF-B in many cases cause activation of NF-B, and this
positive-feedback loop can amplify and perpetuate local inflammatory
responses.13 This suggests that the
AT2/NF-B pathway could be a component of such
an amplification loop, which eventually enhances expression of both
cytokines and AT2. Increased
production of angiotensinogen by NF-B may
additionally enhance the amplification loop.21 As noted
above, stimulation of AT2 promotes
apoptosis, whereas activation of NF-B generally promotes
cell survival. Although this seems contradictory, NF-B can promote
apoptosis by increasing expression of Fas and Fas ligand in
fibroblasts22 or decreasing bcl-2 expression in aortic
endothelial cells.23 This cell-type
specific action of NF-B may in part explain why
AT2 does not promote apoptosis in some
cell types.24 |
Signaling Mechanism of NF-B Activation by Ang II
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TopIntroductionFunctional Roles of the...Signaling Mechanism of NF...Unresolved QuestionsReferences |
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Another interesting aspect of the work by Ruiz-Ortega et al12 is that both AT1 and AT2 are able to activate NF-
B.
AT2 activates protein phosphatases,
including SHP-1, PP2A, and MKP-1, thereby inactivating tyrosine kinases
and mitogen-activated protein kinases stimulated by
AT1.2 It is interesting that NF-B
activation is one of the few examples reported thus far in which
AT1 and AT2 share the
signaling mechanism at least in part (Figure
). Although both
AT1 and AT2 stimulation
cause degradation of inhibitor B (IB),12
an essential step for nuclear translocation of NF-B, the mechanism
leading to IB degradation by AT1 and
AT2 stimulation remains to be clarified.
Degradation of IB depends on phosphorylation of the
two N-terminus serines by IB kinase, and the
phosphorylated IB undergoes polyubiquitination and
proteasome degradation.25 Degradation of IB can be also
mediated by phosphorylation of IB at tyrosine 42 or
by unknown mechanisms involving protein tyrosine
phosphatases.25 26 Therefore, it will be interesting to
determine whether NF-B activation by AT1 and
AT2 is mediated by either IB kinase–dependent
mechanisms or other mechanisms in which tyrosine kinases or
phosphatases (directly or indirectly) modulate IB degradation.
Ruiz-Ortega et al12 suggest that oxygen radicals and
ceramide are common mediators of NF-B activation by
AT1 and AT2. However, how
AT2 stimulates production of oxygen
radicals and ceramide in cardiovascular cell types
remains to be elucidated. |
Unresolved Questions |
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TopIntroductionFunctional Roles of the...Signaling Mechanism of NF...Unresolved QuestionsReferences |
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Several important questions remain unanswered. First, in cultured smooth muscle cells, Ang II–induced increases in MCP-1 and angiotensinogen, well-known targets of NF-
B, were
mediated predominantly by AT1, despite both
AT1 and AT2 stimulation
activating NF-B in this cell type.12 Because
AT1 is the predominant Ang II receptor subtype in
cultured aortic vascular smooth muscle cells, the possibility remains
that these NF-B targets may be regulated more potently by
AT2 when expression of AT2
is upregulated in pathological conditions. It is also possible that
AT1 and AT2 regulate
different molecules through NF-B. For example, the
AT1/NF-B pathway may regulate predominantly
proinflammatory cytokines, whereas the
AT2/NF-B pathway may have different targets.
The mechanisms by which AT1 and
AT2 regulate distinct NF-B targets remain to
be clarified. Because NF-B is known to function in concert with
other transcription factors13 such as AP-1 and C/EBP,
these cofactors may be regulated differentially by
AT1 and AT2.
Another important question is whether the
AT2/NF-B pathway always exerts a beneficial
action in cardiovascular diseases.1 The
answer is not simple, considering that NF-B activation can be both
beneficial and detrimental. For example, NF-B activation is
essential for the development of the cardioprotective effects of
preconditioning.27 On the other hand, many studies have
shown that inhibition of NF-B can also have a salutary effect on
cardiovascular diseases. For example, in vivo transfer
of NF-B decoy oligonucleotides reduces the extent of
myocardial infarction and reperfusion injury.28 29
Inhibition of NF-B reduces Ang II–induced organ damage in the heart
and kidney by preventing inflammatory mediators.30 In the
vasculature, inhibition of NF-B suppresses development of
atherosclerotic lesions by preventing inflammation,31
smooth muscle cell proliferation,32 and dysregulation of
apoptosis.33 In a recent review,
Matsubara1 discussed the potential advantages of shunting
Ang II toward AT2 (during
AT1 blockade) in the treatment of
cardiovascular diseases. This hypothesis is well
supported by the results of a recent study showing that
losartan was associated with a lower mortality rate than
captopril in the treatment of older heart failure
patients.34 It has been shown that cardioprotective
effects of AT1 antagonists in a rat
model of heart failure are prevented by AT2
blockade.35 It will be extremely important to identify the
targets of the AT2/NF-B pathway in each
disease condition and evaluate in which disease states stimulation of
AT2 could be beneficial.
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Acknowledgments |
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The author thanks Dr Stephen F. Vatner for critical reading of this manuscript.
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Footnotes |
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The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
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References |
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TopIntroductionFunctional Roles of the...Signaling Mechanism of NF...Unresolved QuestionsReferences |
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