doi: 10.1161/hh0901.091204
© 2001 American Heart Association, Inc.
Editorial |
Renin-Angiotensin System in Human Failing Hearts
Message From Nonmyocyte Cells to Myocytes
From the Department of Medicine II and Cardiovascular Center, Kansai Medical University, Moriguchi, Osaka, Japan.
Correspondence to Hiroaki Matsubara, Department of Medicine II and Cardiovascular Center, Kansai Medical University, Moriguchi, Osaka 570-8507, Japan. E-mail matsubah{at}takii.kmu.ac.jp
Key Words: angiotensin II • angiotensin receptor • human heart • heart failure • angiotensin-converting enzyme
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Introduction |
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 Top Introduction References |
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The survival benefit conferred by angiotensin-converting enzyme (ACE) inhibitors in patients with heart failure has led to an intense interest in the mechanisms underlying the action of angiotensin II.1 2 However, ACE inhibition therapy does not completely block angiotensin II production, and in some patients angiotensin II remains elevated, in part because of the conversion of angiotensin I to angiotensin II by chymase activity.3 The main two receptors for angiotensin II, AT1 receptor (AT1R) and AT2 receptor (AT2R), are present in the myocardium. Most angiotensin II functions in the cardiovascular system are mediated by AT1R. AT2R has anti-AT1R effects, such as negative chronotropic action or inhibition of interstitial fibrosis, which may play a protective role in development of heart failure.4 Presently, no therapeutic agents that specifically act on AT2R are approved for clinical trials. However, AT1R blockers are available that could shunt the activity of the cardiac renin-angiotensin system toward selective stimulation of beneficial AT2R. Two separate clinical approaches (ELITE-II and RESOLVD) compared ACE inhibitors with AT1R blockers in patients with heart failure.5 6 No significant differences were observed in the beneficial effect of these two classes of agents, and the cardioprotective role of AT2R remains to be determined.
The cardioprotective action of ACE inhibitors and AT1R blockers depends on the expression level of myocardial AT1R and AT2R in patients with heart failure. The first study to examine these levels in human myocardium found no significant changes in total angiotensin II receptor numbers between failing and nonfailing hearts.7 More recent studies in human heart failure have shown downregulation of AT1R,8 9 10 11 12 13 14 either without changes8 9 10 11 12 or with an increase13 14 in AT2R numbers. Measurement of AT1R and AT2R numbers has been analyzed using ligand-binding assays based on membrane fractions from cardiac tissue. Cell type–specific expression patterns of AT1R and AT2R have not yet been defined in failing human hearts.
An important new study of cardiac AT1R density in failing human heart appears in the present issue of Circulation Research. Serneri et al15 isolated myocytes as well as membrane fractions from failing human hearts and found that AT1R density did not change in failing myocytes but decreased in cardiac membrane fractions. This suggests that myocytes remain in endstage failing hearts as potential targets for angiotensin II–mediated effects and that AT1R is selectively downregulated in nonmyocyte cells. Serneri et al15 report that stretch-activated signals attributable to ventricular filling pressure inhibited downregulation of AT1R in myocytes but not in nonmyocytes. In fact, stretching of myocytes from neonatal rat hearts, but not that of fibroblasts, was shown to upregulate AT1R expression.16 Thus, myocytes maintain AT1R numbers even in the failing stage, supporting the efficacy of ACE inhibitors and AT1R blockers in this pathological state.
Serneri et al15 demonstrate that the progression of heart failure is closely associated with a progressive increase in cardiac angiotensin II formation and a strong correlation with the increasing end-diastolic stress. Conversion of angiotensin I to angiotensin II, ACE, and angiotensinogen mRNA levels were significantly increased in failing heart samples, whereas chymase expression did not change. Interestingly, Serneri et al15 also showed that ACE and angiotensinogen mRNAs in the nonfailing hearts were expressed only in trace amounts, whereas their expression was notably enhanced in failing hearts and exclusively localized in nonmyocyte cells. Angiotensin II protein was present mainly in the interstitial region of failing hearts. These findings suggest that in the failing heart stage, angiotensin II was actively processed and released from nonmyocyte cells present in the interstitial regions, leading to the activation of AT1R and AT2R that exists in myocytes as well as nonmyocytes. AT1R and AT2R densities in failing myocytes are <10% of cardiac membrane fractions, suggesting that the receptors are dominantly present in nonmyocyte cells. We have shown using autoradiography that receptors for angiotensin II are localized in fibrous regions rather than in myocardium, and a similar distribution pattern was observed in both nonfailing and failing human hearts.13 AT2R expression was highly localized in fibrous regions, and AT1R was localized in both myocytes and nonmyocytes.13 Serneri et al15 also report that the main fraction of angiotensin II receptors in failing hearts is included in nonmyocyte cells, whereas their expression in myocytes is much less (10% to 20%) than those in nonmyocytes.15 Thus, it seems that the main target of angiotensin II is nonmyocyte cells (mainly fibroblasts) and the effect on myocytes might be less than that on fibroblasts. Perivascular fibrosis of microcoronary arteries occurs in the initial phase of cardiac remodeling, which leads to the decrease in coronary blood flow followed by myocardial ischemia. Inhibition of perivascular fibrosis by blocking angiotensin II–mediated action is likely a main mechanism responsible for cardioprotective action of ACE inhibitors or AT1R blockers, although angiotensin II is known to induce myocyte hypertrophy17 or interstitial fibrosis associated with fibroblast proliferation.18
Cardiac insulin–like growth factor-1 (IGF-1) and endothelin-1 (ET-1) play a critical role in supporting cardiac-adaptive response to hemodynamic overload. Human compensatory hypertrophy attributable to aortic valve disease is associated with an increased myocyte formation of IGF-1 in volume overload and IGF-1 and ET-1 in pressure overload.19 Cardiac production of these growth factors is positively related to myocardial contractility.19 Serneri et al15 additionally demonstrate that angiotensin II induces IGF-1 and ET-1 synthesis by human isolated nonfailing myocytes and that failing myocytes are selectively unable to produce appreciable amounts of IGF-1 and ET-1 in response to angiotensin II stimulation, not withstanding the similar density and binding capacity of angiotensin II receptors. Platelet-derived growth factor synthesis via AT1R was preserved in failing myocytes,15 suggesting a specific impairment of the pathways leading to IGF-1 and ET-1 formation. Although Serneri et al15 could not define the mechanisms responsible for the incapacity of failing myocytes to produce IGF-1 and ET-1, some signaling pathways via AT1R may be interrupted or novel intervening molecules may be generated in failing myocytes to affect the signal transduction.
Recent evidence suggests that local
angiotensin II through AT1R
activates the transcription factor nuclear factor-
B, thereby
promoting expression of numerous genes, including various
cytokines and adhesion
molecules.20 Such
AT1R-mediated transcriptional systems might be
impaired in failing myocytes, and novel transcriptional factors could
be generated.21 Because
AT1R on myocytes is not downregulated in failing
human hearts, the long-lasting excessive angiotensin II
formation can mediate detrimental effects on overloaded or failing
myocytes, including depression of contractility or
impaired relaxation. Thus, the defective response of failing myocytes
to angiotensin II stimulation may reside either in
intracellular signal transduction pathways or in transcription factors.
However, specific studies are required to investigate cellular
functions or biochemical machinery of failing myocytes and
nonmyocytes in response to angiotensin
II.
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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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TopIntroductionReferences |
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