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(Hypertension. 2004;43:1162.)
© 2004 American Heart Association, Inc.

Editorial Commentaries

Cardiac Angiotensin AT₂ Receptor

What Exactly Does It Do?

George W. Booz

From the Cardiovascular Research Institute of the Texas A&M, University System Health Science Center College of Medicine, Scott & White Hospital and Clinic, and the Central Texas Veterans Health Care System, Temple.

Correspondence to George W. Booz, PhD, Texas A&M University System Health Science Center, College of Medicine, Cardiovascular Research Institute, Division of Molecular Cardiology, 1901 South 1st Street, Bldg 205, Temple, TX 76504 E-mail gbooz{at}medicine.tamu.edu

Angiotensin II (Ang II) has multiple actions in the heart that affect cardiac remodeling and contractility, most of which can be attributed to activation of the Ang II type-1 (AT₁) receptor.¹ This 7-transmembrane-domain, G-protein-coupled receptor activates multiple intracellular signaling pathways that encompass calcium, phospholipids, kinases, and reactive oxygen species. But cardiac cells also express a second major Ang II membrane receptor, namely type-2 (AT₂), which despite being cloned more than a decade ago, remains something of an enigma as far as what function it plays in normal or diseased hearts.² AT₁ and AT₂ exhibit only 30% primary sequence homology, but both belong to the class A rhodopsin-like family of G-protein-coupled receptors and have similar high affinities for Ang II in the nanomolar range. However, the similarity ends there. The 2 receptors differ in which heterotrimeric G-proteins they preferentially activate, whether they undergo internalization on ligand binding, and the repertoire of signaling events each activates. In contrast to AT₁, only 4 major signaling mechanisms have been linked to AT₂: activation of protein phosphatases and protein dephosphorylation, regulation of the bradykinin-nitric-oxide-cGMP system, activation of phospholipase A₂ (PLA₂) and arachidonic acid release, and sphingolipid-derived ceramide formation.¹ Which mechanism predominates appears to be cell-type specific.

Because AT₂ couples to phosphatase activation whereas AT₁ activates various kinases, it is not surprising that in a variety of cell types the 2 receptors appear to be mutually antagonistic. In the early 1990s there were many reports demonstrating that Ang II has growth-promoting effects on cardiac cells via AT₁ activation, and some of the early reports for an antagonistic relationship between the 2 receptors demonstrated that AT₂ is growth inhibitory. Early studies found that AT₂ opposes the hypertrophic action of AT₁ on cultured rat cardiac myocytes.^3,4 Shortly thereafter, Bartunek et al were able to show, using the perfused hypertrophied adult rat heart, that inhibition of AT₂ amplifies the immediate growth response of the left ventricle to Ang II.⁵ Their findings are complemented by a recent study showing that AT₂ blockade diminishes the antihypertrophic effects of AT₁ receptor blockade in an adult rat model of pressure-overload cardiac hypertrophy.⁶ However, these studies used receptor blockers, and not all such studies found evidence for an antagonistic relationship between AT₁ and AT₂ on cardiac hypertrophy.² Results using AT₂ knockout mice have made matters more confusing, with studies involving different in vivo models of cardiac remodeling reporting no,⁷ suppressive,⁸ or obligatory⁹ role for AT₂ in the development of pathological hypertrophy.

How is it possible to reconcile these disparate findings? As suggested by Schneider and Lorell,¹⁰ AT₂ function is likely to be context-specific. In other words, the response of a particular cell or tissue to Ang II will be reflective of the ratio of AT₁ to AT₂ at any particular time, which is not static, but changes in the diseased heart. In the hypertrophied rat heart, the ratio of AT₂ to AT₁ is increased, which could explain why in the above cited study by Bartunek et al inhibition of AT₂ did not amplify the growth response to Ang II in normal rat hearts. In failing human hearts, AT₁ levels in the ventricles are decreased, whereas AT₂ expression is either unchanged or increased; in the ventricles of patients with end-stage ischemic heart disease or dilated cardiomyopathy, AT₂ levels are increased in endocardial, interstitial, and infracted regions compared with the noninfarcted myocardium.² Furthermore, whereas AT₁ is the predominant Ang II receptor in animal hearts, studies indicate either that AT₂ predominates in the human heart or that AT₁ and AT₂ are present in nearly equal proportion.^2,11 Thus, context (ie, the AT₁/AT₂ ratio) is an especially important consideration when extrapolating from results obtained with animal models to humans.

The assessment that "context is everything" for resolving the pathophysiological function of AT₂ gives added importance to the study by Alfakih et al that appears in this issue of Hypertension. In a prospective study involving 197 patients with systemic hypertension and 60 normal volunteers, these investigators evaluated whether there was an association between a common intronic polymorphism (–1332 G/A) of the AT₂ gene and left ventricular hypertrophy. The AT₂ gene has 3 exons and 2 introns, with the entire reading frame for AT₂ located on exon 3. The polymorphism site is located 29 bp before exon 2, close to a region important for transcriptional activity. Persons with the G allele have exon 2 missing and less effective transcription of the AT₂ gene. The authors observed a statistical association between the AT₂ (–1332 G) allele and the presence of left ventricular hypertrophy in patients with hypertension, despite the fact that the majority of patients were on antihypertensive medications. Thus, the findings of this study are in keeping with the hypothesis that AT₂ has antigrowth effects on the heart that counterbalance the growth-promoting effects of AT₁. In addition, as noted by the authors, the AT₂ polymorphism might serve as a marker for patients who would benefit more from blockade of the AT₁ receptor.

One premise of the conclusion reached by Alfakih et al is that the function of AT₂ is revealed only under a stress condition, meaning that reduced AT₂ expression during development itself did not set into play some event that results in a greater propensity for cardiac hypertrophy with hypertension. If so, then their study by design defines a role for the cardiac AT₂ receptor in the human heart strictly in context. Of course their study cannot address the issue of whether AT₂ activation has a direct effect on cardiac myocytes that impacts on growth. In fact, the cellular distribution of AT₂ in the human heart is still unsettled, although several studies have identified AT₂ in human cardiac myocytes.¹² Moreover, even if AT₂ does oppose the growth-promoting effects of AT₁ at the level of the cardiac myocyte, the mechanism by which it does so may turn out to be more complicated than originally envisioned. Besides activating potentially antagonistic signaling pathways, AT₂ could perhaps modulate AT₁ function through a direct interaction,¹³ and vice versa. If this hypothesis is correct, than labeling AT₂ antigrowth and AT₁ progrowth would certainly be overly simplistic. An entirely different response to AT₂ activation might be seen at one ratio of AT₁ to AT₂ compared with another. Thus, the recent findings of Lorell and colleagues¹² that targeted overexpression of AT₂ to the ventricles leads to dilated cardiomyopathy with an increase in the size of myocytes and heart failure cannot be construed as being at odds with the findings of Alfakih et al. Finally, one issue not addressed by Alfakih in their discussion is the possibility that reduced AT₂ expression in their patients may have been accompanied by an increase in AT₁ expression and what impact that might have had on the level of cardiac hypertrophy. Others have noted an increase in left ventricular AT₁ expression in AT₂ knockout mice.¹⁴ Perhaps AT₂ counterbalances the actions of AT₁ by impacting on its level of expression.

Evidence indicates that AT₂ is also involved in cardiac fibrosis and electrical remodeling.^2,15 There again, understanding the pathophysiological role that AT₂ plays will require a consideration of the level of interplay between AT₁ and AT₂. Undoubtedly, as with cardiac growth, any answer to the question of what role AT₂ plays in these processes will need to be prefaced with the words "that depends."

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 Full Text (PDF) All Versions of this Article: 43/6/1162    most recent 01.HYP.0000128531.39964.c0v1 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 Booz, G. W. Search for Related Content PubMed PubMed Citation Articles by Booz, G. W. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Related Collections Other myocardial biology Hypertrophy ACE/Angiotension receptors