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(Circulation. 1997;95:1104-1107.)
© 1997 American Heart Association, Inc.

Articles

Downregulation of Angiotensin II Receptor Type 1 in Heart Failure

A Process of Adaptation or Deterioration?

Masahiko Kurabayashi, MD, PhD; Yoshio Yazaki, MD, PhD

From the Third Department of Internal Medicine, Faculty of Medicine, University of Tokyo (Japan).

Correspondence to Yoshio Yazaki, MD, PhD, The Third Department of Internal Medicine, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113, Japan.

Key Words: Editorials • receptors, adrenergic, beta • angiotensin • heart failure

	Introduction

Top Introduction References

 
Among the major consequences of reduced cardiac performance is the neurohumoral response, mediated primarily by activation of the sympathetic-adrenergic system and the renin-angiotensin system (RAS). These responses may contribute to maintain homeostasis and are considered to be adaptive mechanisms to a fall in cardiac output for the short term. If sustained in heart failure, however, the cellular and molecular abnormality within the heart induced by these changes can cause detrimental effects on cardiac function and thus plays a critical part in determining the poor prognosis of this condition.¹ It is now apparent that cardiac hypertrophy, one of the most important responses of the failing heart, is a complex process that is both beneficial and detrimental. Although a growing number of molecular changes have been recognized in both compensatory hypertrophy and end-stage heart failure, it is poorly understood whether such changes contribute to or compensate for the deterioration of the heart or are simply associated with the failure and have nothing to do with the relevant processes. Thus, understanding the nature and mechanisms for the transition to heart failure after chronic overload has been a focus of considerable attention.

During the last several years we have witnessed a great advance in our understanding with respect to the pathophysiological role of the local RAS in the heart. Evidence presented to date indicates that the local RAS is selectively activated despite the normal circulating RAS in the overloaded heart associated with hemodynamic overload and myocardial infarction. Since angiotensin II exerts direct cardiac effects, including trophic effect, long-term activation of cardiac RAS leads to cardiac hypertrophy independent of circulating levels of angiotensin II.^{2 3} Angiotensin II has also been shown to elicit a mitogenic response in neonatal and adult cardiac fibroblasts that may largely contribute to cardiac hypertrophy as well as interstitial and perivascular fibrosis in the myocardium. Although a direct relation between the nature of the overload and the stimulation of the cardiac RAS has not been evaluated, an elevation of systolic wall stress has been postulated to represent an important determinant of RAS activation. This notion will strengthen the argument that an increase in wall tension activates the RAS, leading to the increase in intracardiac angiotensin II production, which in turn contributes to myocardial remodeling and to increased diastolic stiffness. These models may explain the well-documented beneficial effect of ACE inhibitors on cardiac function in both experimental and clinical settings.

The demonstration of RAS activation in human heart is important because species uniqueness of the pathways of angiotensin II production may preclude direct transfer of information obtained in laboratory animal models. The activation of cardiac ACE gene expression in human heart failure has been confirmed in a study using the quantitative method of competitive RNA-PCR (RNA-polymerase chain reaction).⁴ This study demonstrates that expression of cardiac ACE is upregulated in failing human hearts, while in the same tissues the gene expression of chymase remains unchanged. Chymase is the chymotrypsin-like serine proteinase, which is the most efficient and specific angiotensin II–forming enzyme described and not inhibited by ACE inhibitors. No significant differences of chymase mRNA and immunoreactivity are observed between normal and failing human hearts.⁵ However, we need to await the specific inhibitors of human chymase to understand the functional significance of the chymase in normal and failing human hearts. Another open question is the potential change in angiotensin II receptor subtypes in human heart failure. Only a few studies have examined distribution and regulation of human myocardial angiotensin II receptors in heart failure.^{6 7} The information obtained from those reports is inconsistent, and this issue remains to be more thoroughly studied.

In this issue of Circulation, Asano et al⁸ have again drawn attention to the importance of the cardiac RAS and provided additional important details concerning the regulation of angiotensin II receptors in failing hearts. These investigators performed quantitative analysis of these receptors in membranes from human failing myocardium by radioligand binding assays. They demonstrated that AT₁-receptor but not AT₂-receptor density is significantly decreased in the ventricles with idiopathic dilated cardiomyopathy but not with ischemic cardiomyopathy. They have also shown that AT₁-receptor density is correlated with the ß₁-adrenergic receptor but not ß₂-adrenergic receptor density. It is of interest to note that downregulation of the AT₁- and ß₁-receptors may not be disease specific but may correlate to the severity of heart failure. Although the results in this study do not document a causal relation between the downregulation of AT₁-receptor and mechanical load on the ventricle, significant downregulation only in severely impaired left ventricles may imply that AT₁-receptors are determinants for the shift to end-stage heart failure. This study has several strengths. First, a fairly large number of samples was included in the study, and second, they performed cutting-edge techniques of in situ reverse transcription–PCR to localize AT₁-receptor mRNA on myocytes and interstitial vessel wall. Unfortunately, the localization of the AT₂-receptor has not been shown in this study. This issue is interesting because adult rat ventricular myocytes express exclusively the AT₁-receptor,⁹ whereas ventricular tissue possesses both AT₁- and AT₂-receptors.¹⁰

Importantly, it should be recognized that some of the findings in this study appear to be in contrast with the recent results reported by others. The work by Regitz-Zagrosek et al⁷ demonstrated that AT₂ is the predominant subtype in the normal human heart, and both AT₁- and AT₂-receptors are downregulated in failing human heart. Measurement of the receptor density in the myocardium, especially in membrane preparations from heart homogenates, should be interpreted with caution because heart is composed of several tissue types, including blood vessels, connective tissue, and nerves. In addition, myocardial necrosis and fibrosis, which generally accompany the failing myocardium, could alter the receptor subtype composition in heart homogenates, since fibroblasts and cardiomyocytes have a different population of receptors.¹¹ Furthermore, with hypertrophy, it is difficult to distinguish actual downregulation of the receptor from a dilution of the receptor on the plasma membrane. One approach to circumvent these problems may be quantitative autoradiography, which can offer geographic resolution of receptor subtypes in mixed tissue types not possible with traditional membrane preparations.

While this study is descriptive in nature, the finding of selective downregulation of AT₁-receptor in heart failure raises an important question regarding its physiological significance. Does it contribute to or compensate for the deterioration of the heart failure? Since ACE inhibitors improve survival in patients with chronic congestive heart failure and successfully prevent remodeling of the left ventricle after myocardial infarction, reduction of the growth-promoting effects can have a beneficial effect on failing heart. In addition, although angiotensin II mediates a positive inotropic effect in animal models and human atrial myocardium, recent work¹² has documented that angiotensin II may rather exacerbate the loss of cardiac contractility in the failing heart, possibly due to the interaction of angiotensin II with the impaired calcium handling seen in failing heart. Thus, a downregulation of the AT₁-receptor can attenuate the negative inotropic effect of angiotensin II on depressed contractile performance. Viewed from these perspectives, the downregulation of the AT₁-receptor, which can blunt the response of the failing heart to enhanced production of angiotensin II, is likely to be favorable in patients with heart failure.

However, downregulation of the AT₁-receptor but not the AT₂-receptor may also cause deleterious effects on cardiac performance because downregulation of the AT₁-receptor results in an increase in available angiotensin II levels, and effects mediated by AT₂ can become exaggerated. Although we still do not know the exact physiological function of the AT₂-receptor in humans, this concern comes from the studies in vitro, which suggest that AT₂ may play a role in inhibiting cellular growth and in inducing apoptosis¹³ by antagonizing the effects of the AT₁-receptor. Furthermore, studies in rats have suggested that AT₂ antagonists may have favorable effects on postinfarction ventricular remodeling.¹⁴ This is one explanation for why AT₁-receptor antagonists may be less effective than ACE inhibitors in some¹⁵ but not all¹⁶ animal models of left ventricular dysfunction. Obviously, future studies on the functional role and signal transduction mechanisms of the AT₂-receptor in heart failure will be required to understand the functional significance of the selective downregulation of AT₁-receptor in human heart failure.

The report by Asano et al⁸ highlights the probability that angiotensin II receptors themselves may have important regulatory functions in their own right in heart failure. What, then, are the factors regulating the differential expression of angiotensin II receptor subtypes? To address this important question, it seems to be relevant to consider the accumulating knowledge concerning the molecular mechanisms underlying regulation of ß-adrenergic receptor subtypes in heart failure because the AT₁-receptor belongs to the superfamily of G-protein–coupled receptors with seven-membrane–spanning domains, ^{17 18} as is the case for ß-adrenergic receptors, and there exists a positive correlation between AT₁- and ß₁-receptor density in failing myocardium, as implied by Asano et al, suggesting that the mechanisms for downregulation of both receptors are partly shared or linked to each other.

It has been long known that in heart failure, there is often a significant decrease in total cellular receptor density of ß₁-receptors with no decrease in ß₂-receptors.^{19 20} On the other hand, evidence presented to date demonstrates that catecholamine stimulation generally downregulates the ß₂-receptor to a much greater extent than the ß₁-receptor in the heart, which is the opposite phenomenon observed in heart failure. These alterations have been considered a consequence of the increased stimulation of ß₁-receptors by the sympathetic neurotransmitter norepinephrine and, to a lesser extent, of stimulation of ß₂-receptors by high plasma catecholamine levels associated with this disorder. Nevertheless, the underlying mechanism of differential downregulation of ß-receptor subtypes by catecholamines remains obscure. Increasing evidence suggests that these effects seem to be dependent on their molecular difference because ß-receptors are regulated by agonist in a similar manner regardless of the cell types or tissue compartment. Much less is known about the mechanism of selective downregulation of the ß₁-receptor in heart failure. In the case of agonist-dependent desensitization, it is becoming evident that ß-adrenergic receptor protein kinase (ßARK), a member of the G-protein–coupled receptor kinase (GRK) family, having a high degree of specificity for ß₁- and ß₂-receptors, plays a major role in uncoupling of ß-receptors.²¹ Activation of the ß-receptor leads to the phosphorylation of ßARK, which in turn phosphorylates the ß-receptor. Inactivation of the ß-receptor by ßARK involves the inhibitor protein called ß-arrestin, which blocks the interaction between the phosphorylated ß-receptor and the G protein. It has been shown that ßARK mRNA but not ß-arrestin mRNA is increased in chronic heart failure in humans.²² Furthermore, cardiac overexpression of ßARK in transgenic mice attenuates the inotropic response to isoproterenol and conversely, mice expressing the ßARK inhibitor displayed enhanced myocardial contractility.²³ These studies support the concept that increased myocardial ßARK expression may play a major role in the desensitization of myocardial ß-receptor characteristic to heart failure.

In heart failure, although the decrease in receptor number may partly be the result of internalization followed by degradation of the receptor protein, it now seems clear that this is partly due to a specific decrease in the expression of the ß₁-receptor gene demonstrated both at the protein and mRNA levels.²⁴ Whether a decrease in ß₁-receptor mRNA is due to the decrease in transcriptional rate or to enhanced message degradation has not yet been determined. Evidence that posttranscriptional mechanisms regulate adrenergic receptor gene expression has been provided.²⁵ The ß₂-receptor cDNA driven by viral promoter is also dramatically downregulated by cAMP.²⁶ However, this is not the case for the ß₁-receptor, and thus it does not account for the decreased level of ß₁-receptor mRNA. Studies by coverslip autoradiographic techniques have provided more convincing evidence that suggests that ß-agonist infusion induces a selective downregulation of the ß₂-receptor on cardiomyocytes.²⁷ Thus, most of the studies indicate that an increase in plasma level of catecholamines is not the mechanism of selective ß₁-receptor downregulation.

The regulation of AT₁-receptor gene expression is of intense current interest. Although Asano et al do not provide information regarding the potential mechanisms involved, limited available evidence from studies in vitro with vascular smooth muscle cells or rat mesangial cells in culture suggests that angiotensin II may negatively regulate the expression of its own receptor. Exposure of the mesangial cells to angiotensin II markedly suppressed AT_1A mRNA.²⁸ Although the study using the cardiomyocytes is absolutely warranted, downregulation of AT₁-receptor is likely to be attributed to this mechanism because local activation of cardiac RAS leads to the enhanced production of angiotensin II in failing ventricles. However, this model seems to be oversimplified because myocardial AT₁-receptor is upregulated 1 week after infarction in the noninfarcted areas of viable myocardium,⁹ where angiotensin II production should be increased. In any case, the possibility that expression of the AT₁-receptor gene is regulated by angiotensin II awaits experimental verification in cardiomyocytes.

This homologous downregulation of the AT₁-receptor is reminiscent of the situation for ß₂-receptor downregulation, where either ß-adrenergic agonists or cAMP analogues produced a loss of receptor-binding sites that was accomplished by substantial decreases of ß₂-receptor mRNA levels.²⁹ Because depletion of protein kinase C by the prolonged pretreatment with tissue plasminogen activator has no effect on angiotensin II–induced downregulation, and elevation of intracellular Ca²⁺ by the calcium ionophore A23187 failed to mimic the downregulating effect of angiotensin II, homologous downregulation by angiotensin II of its AT₁-receptor gene expression is not mediated by the elevated cytosolic Ca²⁺ or protein kinase C activation,²⁸ as expected from the well-known downstream effects of angiotensin II binding. The homologous downregulation of AT₁ mRNA cannot be explained without invoking another mechanism, which may exert a negative modulatory effect in the 5'-flanking region of the AT_1A gene. It should also be acknowledged that agents that elevate intracellular cAMP also downregulate AT₁-receptor mRNA expression.²⁸ In this regard, it is provocative to speculate that increase in adrenergic sympathetic activity may contribute to the AT₁ downregulation in heart failure, since angiotensin II may exert its action on the myocardium indirectly by facilitating the release of neurotransmitters from adrenergic cardiac presynaptic nerve terminals.³⁰

In conclusion, because of the remarkable development of cardiovascular molecular biology, striking progress has been made during the past few years with respect to our understanding of the pathophysiology of heart failure. Today we stand at the threshold of exploiting new strategies to improve the poor prognosis of this disorder. To accomplish this goal, it is prerequisite to understand at the molecular level the fundamental process for a progression from adaptation to heart failure. It is generally agreed that the mechanisms that initially aid survival in the patients with acute heart failure can become deleterious when they are sustained. Cardioreparative properties of ACE inhibitors lead us to speculate that activation of cardiac RAS may be considered as a critical process. Demonstration of a significant downregulation of AT₁-receptor in failing heart strengthens the argument for the role of RAS for the progression of cardiac dysfunction. Increased concentrations of agonists are the most likely explanation for downregulation of the AT₁-receptors, but the fact that overloaded myocardium can produce a number of peptide growth factors, cytokines, and nitric oxide raises the possibility that other factors may be involved in the regulation. Dissection of the molecular network of these neurohumoral factors may lead us to uncover the mechanisms of the transition to heart failure and allow us to develop new strategies to prevent the progression of heart failure.

	Footnotes

 
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.

	References

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This Article Extract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kurabayashi, M. Articles by Yazaki, Y. Search for Related Content PubMed PubMed Citation Articles by Kurabayashi, M. Articles by Yazaki, Y.