EDITORIAL COMMENT
An ACE in the HoleAlternative Pathways of the Renin Angiotensin System and Their Potential Role in Cardiac Remodeling*
Barry Greenberg, MD, FACC*
University of California, San Diego, California.
* Reprint requests and correspondence: Dr. Barry Greenberg, Professor of Medicine, Director, Advanced Heart Failure Treatment Program, University of California, San Diego, 200 West Arbor Street, San Diego, California 92103-8411. (Email: bgreenberg{at}ucsd.edu).
Key Words: renin-angiotensin system • ACE2 • heart failure • cardiac remodeling • angiotensin
There is compelling evidence that the renin angiotensin system (RAS) plays a major role both in maintaining cardiovascular homeostasis and the pathogenesis of cardiovascular diseases ranging from hypertension to heart failure. In the classical RAS (depicted in Fig. 1), angiotensinogen released into the circulation from the liver is enzymatically degraded by renin that originated in the kidney to generate the inactive precursor molecule angiotensin (Ang I). When this decapeptide comes into contact with angiotensin-converting enzyme (ACE) at the endothelial surface of blood vessels, the 2 terminal amino acids are cleaved from the carboxy terminus, giving rise to Ang II, the main effector molecule of the RAS. Through interactions with specific receptors, and in particular its type 1 or AT1 receptor, Ang II stimulates a wide variety of signaling pathways in the heart, blood vessels, kidneys, and brain to initiate most of the physiologic and pathophysiologic effects that have been attributed to the RAS.
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Figure 1 A Novel Pathway of the RAS Involving ACE2
Classical and alternative pathways of the renin angiotensin system. Angiotensin-converting enzyme (ACE)2 activity alters the ratio between Angiotensin (Ang) II and Ang(1-7) by cleaving the terminal amino acid from either Ang I or Ang II. As opposed to Ang II, which has pre-growth and vasoconstricting properties, Ang(1-7) has been shown to have antigrowth and vasodilatory properties. RAS = renin angiotensin system. Figure illustration by Rob Flewell.
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During the past 2 decades we have learned, however, that the RAS is considerably more complex than the system just described. Many cells are able to generate components of the RAS, with the result being the capacity for local Ang II production in organs throughout the body (1). A cardiac RAS has been detected, although in this case, renin activity may be extracted from the blood rather than produced locally in the heart itself. Alternative pathways for converting Ang I to II that exist in cardiac tissue further complicate the picture. In addition, Ang receptors other than the AT1 receptor have been identified, though their exact role remains controversial.
The importance of the RAS in heart failure is well established. Plasma renin activity is increased during the course of the disease (often in association with the presence of symptoms or in response to treatment with diuretics) (2), and the systemic effects of Ang II, which include peripheral arterial vasoconstriction and salt and water retention, contribute to the heart failure phenotype. Maladaptive cardiac remodeling has been recognized as the underlying process that leads to the progression of heart failure. Remodeling is initiated in response to injury to the heart, such as what occurs after a myocardial infarction (MI), and it involves a complex series of events that result in eccentric hypertrophy of the left ventricle, with increases in both volume and mass, increased sphericity of the chamber, diffuse myocardial fibrosis, and the development of secondary mitral insufficiency. These alterations in the gross morphology of the heart, along with changes in cardiomyocyte and cardiac fibroblast structure and function, cause progressive deterioration in cardiac performance and ultimately to the development of heart failure. The local cardiac RAS has been shown to play a particularly important role in this process. Angiotensin II production is increased within the remodeling heart (3) and increased density of the AT1 receptor on cardiac cells further enhances the progrowth and fibrotic effects of the peptide (4). Studies performed in experimental animal models and in human patients have shown that strategies designed to block either the production or effects of Ang II inhibit maladaptive cardiac remodeling (5) and significantly reduce heart failure morbidity and mortality (6).
The discovery of a homolog of ACE that has been termed ACE2 raises the exciting possibility that additional alternative pathways of the RAS might be involved in the regulation of this system (7). Both ACE and ACE2 are type 1 ectoenzymes, which are anchored to the cell membrane with their enzymatic domains residing exterior to the cell surface. The activity of ACE2 is impervious to classical ACE inhibitors, although there is evidence that these agents, as well as angiotensin receptor blockers, increase ACE2 gene expression (8). Although ACE2 can act on a variety of factors (some of which are noted in Fig. 1), its preferred substrate appears to be Ang II, from which it cleaves the terminal amino acid to form Ang(1-7). The cellular effects of Ang(1-7) are mediated by a receptor (or receptors) that is unique from the AT1 or AT2 receptor subtypes, and there is evidence that many of these involve the G-protein–coupled 7 transmembrane domain Mas receptor (9). In cardiac myocytes, Ang II has been reported to have antihypertrophic effects (10), whereas in cardiac fibroblasts, the heptapeptide inhibits collagen production, expression of "secondary" growth factor genes, and Ang II-stimulated cardiomyocyte hypertrophy that is dependent on factors released from cardiac fibroblasts (11).
Thus, by reducing concentrations of Ang II, which has progrowth and profibrotic effects, and increasing the generation of Ang(1-7), ACE2 could have a beneficial role in the failing heart by restraining or even reversing cardiac remodeling. In support of this possibility is evidence that deletion of the ACE2 gene leads to the development of heart failure and that this effect can be inhibited by further deletion of the ACE gene (12). Moreover, in experimental models Ang(1-7) has been reported to inhibit Ang II-stimulated cardiac remodeling (13) and to improve cardiac function in the post-MI remodeling heart (14).
The role of ACE2 in the human heart remains uncertain. Recent evidence that ACE2 gene expression is increased in both the post-MI and the failing human heart (15,16) supports the possibility that the counter-regulatory effects of this enzyme may be enhanced in certain pathophysiologic settings. In this issue of the Journal, Epelman et al. (17) report that, in a cohort of heart failure patients, ACE2 activity in plasma is increased and that these changes were not dependent on etiology (e.g., ischemic vs. nonischemic). Moreover, ACE2 levels appear to increase in a step-wise fashion as the severity of heart failure progresses, as indicated by both New York Heart Association functional class status and by levels of B-type natriuretic peptide. These exciting new findings demonstrating that plasma ACE2 activity is increased in heart failure patients suggest that the production and/or processing of this enzyme are modified as part of the disease process, and they raise the intriguing possibility that changes in ACE2 activity could be involved in altering the ratio between Ang II and Ang(1-7) and their resultant effects on cardiac cell structure and function.
Although the observations of Epelman et al. (17) are a potentially important step forward, the findings should be placed in the context of what is known about ACE2 and how it is processed. The activity of ACE2 was measured in plasma, and there is no indication from which tissue the greater level of enzyme activity might have originated, nor is it known which step in the processing of ACE2 might have been altered. It is possible that the changes observed in these patients could have been the result of increases in either ACE2 gene expression, translation into protein, intracellular processing and delivery of the mature enzyme to the cell surface, and/or its subsequent cleavage from the cell membrane. Decreased breakdown of the enzyme in the circulation could also be involved. The possibility that changes in ACE2 activity in the plasma are due to increased cleavage is particularly intriguing, however, because the activity of tumor necrosis factor- –converting enzyme (i.e., TACE), an enzyme that has been identified as playing a role in ACE2 cleavage (18), is increased in the setting of heart failure (19). If that does turn out to be case, it is possible that the increases in plasma ACE2 level could indicate that the potentially protective regulatory activity of the enzyme within the myocardium has been reduced and balance between factors promoting and inhibiting remodeling has been shifted in an unfavorable direction.
There is clearly much more work to be done in this area. The value of the report by Epelman et al. (17) is that it now turns our attention to the possibility that ACE2 may indeed be a "player" in the complex series of events that are responsible for the development and progression of heart failure. As studies looking at the effects of regulating ACE2 activity in the remodeling heart progress over time, we may well find that we have been presented with a novel therapeutic target for the treatment of heart failure. If so, having an ACE (or more correctly an ACE2) in the hole may be as welcome to clinicians as having the proverbial "ace in the hole" is to the individual sitting at the poker table.
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Footnotes
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* Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. 
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References
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