Published online before print March 24, 2003, doi: 10.1161/01.HYP.0000063886.71596.C8
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(Hypertension. 2003;41:871.)
© 2003 American Heart Association, Inc.
Editorial Commentary |
Hypothesis
ACE2 Modulates Blood Pressure in the Mammalian Organism
From the Laboratory for Molecular Medicine and Israeli Rat Genome Center, Department of Nephrology and Hypertension, Faculty of Health Sciences, Ben-Gurion University Barzilai Medical Center Campus, Ashkelon, Israel.
Correspondence to Yoram Yagil, MD, Laboratory for Molecular Medicine and Israeli Rat Genome Center, Department of Nephrology and Hypertension, Barzilai Medical Center, Ashkelon 78306, Israel. E-mail labmomed{at}bgumail.bgu.ac.il Internet www.irgc.co.il
The renin-angiotensin system (RAS) is currently considered a central regulator of blood pressure in the mammalian organism. Even though renin was first described in 1898, it was only in the late 1970s and early 1980s that the important contribution of the RAS to mammalian physiology began to be truly recognized. Any doubts that may have arisen as to its relative importance and contribution to cardiovascular disease in general, and to hypertension in particular, were totally dissipated with the advent of angiotensin-converting enzyme (ACE) inhibition for clinical and therapeutic use. It is now well established that hyperactivation of the RAS invariably leads to hypertension and to a number of other adverse cardiovascular effects that can be, at least in part, prevented by ACE inhibition or angiotensin receptor blockade. With the recently discovered angiotensin-converting enzyme 2 (ACE2),1–3 it appears that a new unexpected direction is unfolding in the RAS paradigm which will change altogether our perception of how this important system works.
Our knowledge of RAS has led us until recently to focus primarily on one major axis of the system that is initiated by angiotensinogen, and that is followed by generation of angiotensin I (Ang I) through the catalytic action of renin, hydrolysis and removal of 2 amino acids, primarily by the action of the dipeptidase ACE to yield angiotensin II (Ang II), and occupation of the angiotensin receptors. Ang II is, among its other known biological effects, a most potent vasoconstrictor which can induce hypertension. In this axis, ACE has been looked on as a central modulator of the system and consequently has been targeted with a high degree of success by the pharmaceutical industry. Recent data lead us to realize that this axis represents only 1 of 2 arms of the renin-angiotensin system. The second arm is also initiated by angiotensinogen, but is followed by hydrolysis of Ang I to angiotensin 1-9 (Ang-[1-9]) through the catalytic action of the newly discovered monopeptidase ACE21–3 (Figure). Ang-(1-9), whose activity on the vascular system is not known, is hydrolyzed further and looses 2 amino acids by the action of ACE to generate angiotensin 1-7 (Ang-[1-7]), a potent vasodilator peptide that has generated considerable interest during the past decade. Ang-(1-7) can also be generated directly from Ang I by endopeptidases other than ACE2 and ACE, including neprilsyn, prolyl endopeptidase, and thimet oligopeptidase, but we shall not consider these alternative pathways in the current discussion because their relevance to the ACE2 blood pressure hypothesis is not clear at this time. An additional important action of ACE2, which connects downstream the 2 distinct arms of the RAS, is the hydrolysis of Ang II and removal of one additional amino acid, also producing Ang-(1-7). In fact, the ACE2 catalytic efficiency is 
400-fold higher with Ang II as a substrate than with Ang I.3 In this second arm of the renin-angiotensin system, ACE2, a zinc metalloprotease with carboxypeptidase activity, appears to emerge as a central player and thus becomes a major new target for hypertension and pharmaceutical research.
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We currently hypothesize that the recently uncovered and long overlooked second arm of the renin-angiotensin system, which depends heavily on ACE2 activity and Ang-(1-7) generation, is a counter-regulator of the first arm. ACE2, through the generation of the vasodilator Ang-(1-7) and by hydrolyzing part of Ang II, counterbalances the vasopressor effect of ACE that is mediated by Ang II. We further hypothesize that, under normal conditions, a frail balance prevails between the 2 arms of the renin-angiotensin system, maintaining arterial vessel tonus at a steady state and resulting in normotension. Any imbalance between the 2 arms of the system can result either in hypertension or in hypotension.
The hypothesis that links ACE2 to systemic arterial pressure is based, among others, on several key experimental observations. The first major observation was in model systems of experimental hypertension in which ACE2 gene expression was shown to be decreased in the hypertensive strain when compared with the normotensive control. Crackower et al4 reported in the Sabra rat model of salt-sensitive hypertension that under baseline nonstimulated conditions, ACE2 mRNA and protein levels are diminished in the hypertension-prone SBH/y strain when compared with the hypertension-resistant SBN/y strain. Baseline systolic blood pressure is 10 to 20 mm Hg higher in the Sabra hypertension-prone SBH/y strain than in hypertension-resistant SBN/y rat.5 These latter findings are consistent with the ACE2 hypothesis, because ACE2 levels that are lower in SBH/y could explain the higher arterial pressure, whereas ACE2 levels that are higher in SBN/y could account for lower blood pressure. Crackower et al4 also reported that, during salt-loading, a well-established hypertensive stimulus in the Sabra model, ACE2 levels are diminished even further in SBH/y, which becomes overtly hypertensive, whereas they remain unchanged in SBN/y, which remains normotensive.4,5 The hypertensive response in SBH/y that lack ACE2 is consistent with the ACE2 hypothesis, whereas the continuing normotension in SBN/y is consistent with a "protective" effect of ACE2 that confers "resistance" to the development of hypertension. Equivalent findings were reported by Crackower et al4 also in additional models of hypertension. In the spontaneously hypertensive (SHR) and spontaneously hypertensive stroke-prone (SHRSP) rats that develop hypertension spontaneously without the need for a hypertensive stimulus, ACE2 expression is consistently lower in the hypertensive than in the normotensive Wistar Kyoto (WKY) control. These data in SHR and SHRSP are consistent with the ACE2 hypothesis, because these strains that exhibit a relative lack of the vasodilator effect of ACE2 develop spontaneous hypertension, whereas, in WKY that remain normotensive, higher ACE2 expression could account for the "resistance" to hypertension.
The second important observation, also reported by Crackower et al,4 was that the ACE2 gene maps to hypertension-related quantitative trait loci (QTLs) that have been previously detected by linkage analysis in the Sabra, SHR, and SHRSP rat models of hypertension. Although these QTLs carried a significant LOD score that suggested the presence of a hypertension-related gene within the chromosomal span demarcated by the QTLs, none of the groups working in the field had been able to pinpoint that gene. ACE2 could well be that previously unidentified gene.
The third set of relevant experimental observations was reported very recently by Allred et al6 in an abstract describing that, in knockout mice lacking the ACE2 gene (ace2-/ace2-), baseline blood pressure is 10 mm Hg higher than in normal mice (ace2+/ace2+), and that during intravenous infusion of Ang II, the pressor response is significantly enhanced in ace2-/ace2- compared with normal mice. The higher baseline blood pressure in ACE2-deficient mice is consistent with the findings in the Sabra model, in which SBH/y with the lower ACE2 expression had higher baseline blood pressure.
Taken together, these new experimental data along with a large body of work on the metabolic pathways and physiological effects of the angiotensins carried out during the past decade, lead us to hypothesize that ACE2 counter-regulates Ang II–induced vasoconstriction through an Ang-(1-7)–induced vasodilator effect. In the relative absence of ACE2, an Ang II effect predominates, leading to vasoconstriction and hypertension. In a state in which ACE2 is expressed "sufficiently," normotension prevails as Ang II levels and consequent activity are diminished; the vasoconstrictive effect of the remaining Ang II is counteracted by the vasodilator Ang-(1–7). In a state in which ACE2 is expressed in excess, hypotension develops. Thus, the ACE2 hypothesis can explain, at least in part, the full blood pressure range that consists of hypertension, normotension, and hypotension.
A dual counter-regulatory "system within a system" that allows both stimulation and inhibition of the same target effector is not strange to the biology of the mammalian organism. Such a dual system even seems logical, because a built-in "system within a system" allows balancing between 2 opposing forces, favoring homeostasis. In relation to the cardiovascular system, this dual arm within the renin-angiotensin system appears to create an inner balance between pressor and depressor effects, favoring under normal conditions a normotensive homeostasis. It is only when an imbalance occurs, as a result of some pathological process, that hypertension or hypotension occur.
What are the weak points of this hypothesis? For one, it is unclear what the relative in vivo contribution of the "alternative" arm of the Ang I metabolic pathway is. How much of Ang I in the live organism is catalyzed by ACE to Ang II relative to the amount that is catalyzed by ACE2 to Ang-(1-9) is unknown and needs to be further investigated under a variety of physiological and pathophysiological conditions. The unknown magnitude of the vasodilator effect of Ang-(1-7) per se appears to be a second weak link in the ACE2 hypothesis. Recent studies by Iyer et al,7 taken together with additional studies carried out mostly by the same group over the past decade, appear to have partially resolved this issue and confirm that Ang-(1-7) is indeed a potent vasodilator. The relative vasodilator effect of Ang-(1-7) in relation to the vasoconstrictive effect of Ang II nonetheless still remains unclear. Third, the level of ACE2 expression in humans is unknown. Is ACE2 expression diminished in humans with hypertension, or alternatively, is ACE2 expression increased in normotensive individuals? Is ACE2 overexpressed in humans with hypotension? The difficulty in answering these questions arises from the need to measure either ACE2 expression directly or indirectly by measuring its effector product, Ang-(1-7). One problem is that ACE2 is expressed the most in the kidneys and only to a lesser extent in other organ systems. Measuring ACE2 expression in normal human kidneys is not feasible. It may become possible, however, to eventually measure ACE2 levels in the urine. Such an assay is not available yet. Measuring Ang-(1-7) levels in the circulation, an indirect measure of ACE2 levels and activity, appears also to be extremely difficult because of a very short half-life of this peptide in the circulation.8 The alternative will be to measure Ang-(1-7) levels in the urine, which is feasible but has not been done yet in conjunction with ACE2.
If the ACE2 hypothesis is confirmed, then ACE2 becomes a primary target for the prevention and treatment of hypertension, but also of hypotension. It appears, though, that sufficient data has already been generated for the pharmaceutical industry to conclude that ACE2 is indeed a promising enough molecule to warrant research aiming at modulating ACE2 expression and activity. Millennium Inc has, in fact, developed over the course of the past year an inhibitor of ACE2.9 Although no publications are yet available on the effect of this inhibitor on blood pressure, we predict that ACE2 inhibition would tend to increase blood pressure, either by increasing baseline blood pressure or by rendering individuals more susceptible to hypertensive stimuli such as salt-loading or any hyper-reninemic state with increased Ang II production. We do predict, though, that ACE2 inhibition might become useful in the treatment of symptomatic hypotension rather than hypertension. Based on our current state of knowledge and the ACE2 hypothesis, it would seem that for hypertension a more productive therapeutic avenue would be to try to induce ACE2 expression and activity. A search is undoubtedly on its way for such compounds. In fact, one such compound, omapatrilat, seems already to be available, at least for the experimental setup. Omapatrilat, the first generation of mixed vasopeptidase inhibitors, has already been shown to stimulate ACE2 expression and activity, leading to increased Ang-(1-7) levels.10,11 It is tempting to speculate that part of the hypotensive effect of omapatrilat is dependent on its stimulatory effect on ACE2. Unfortunately, Omapatrilat has been ruled out as a therapeutic agent for human use because of serious adverse effects. We are confident that other more specific ACE2-targeted compounds will emerge during the next few years that will stimulate ACE2 expression and activity and that will allow the specific application of our hypothesis to therapeutic use in humans.
It is of interest to try to predict, along the lines of the ACE2 hypothesis, the interaction of ACE inhibition, a commonly used therapeutic measure, with ACE2 activity. ACE inhibition diminishes Ang II production, but would also tend to diminish Ang-(1-7) generation by preventing the hydrolysis of ACE2-mediated Ang-(1-9). These effects would be counteracted to some degree by the fact that some Ang-(1-7) may continue to be produced from Ang I directly by other endopeptidases, that ACE activity is not altogether inhibited by ACE inhibitors, and that Ang II continues to be produced also by non-ACE–mediated pathways. In this latter case, ACE2 activity would reduce the residual Ang II levels by hydrolysis to Ang-(1-7) and enhance the hypotensive effect of ACE inhibition. In addition, because ACE appears to be the primary enzyme for metabolizing Ang-(1-7), inhibiting ACE would prevent Ang-(1-7) metabolism and increase Ang-(1-7) levels. The fact is that ACE inhibition, indeed, increases urinary Ang-(1-7) levels.12 We predict, therefore, that ACE inhibition and ACE2 stimulation would be synergistic, if not additive, in inducing vasodilation and reducing blood pressure. We also predict that ACE2 stimulation would enhance the hypotensive effect of angiotensin receptor blockers by reducing Ang II receptor substrate.
In conclusion, we propose that, from here on, when targeting the RAS, one should consider not only the traditional ACE-mediated arm of the RAS, but also take into account the newly uncovered ACE2-mediated pathway, as both arms may be affected. The discovery and uncovering of the ACE2 arm of the RAS sheds new light on our understanding of the pathophysiology of blood pressure regulation and opens new possibilities for the treatment of hypertension and perhaps hypotension. But should one limit these conclusions with regards to ACE2 only to blood pressure regulation? Most likely not. Because the renin-angiotensin system has been implicated in the physiology and pathophysiology of many organ systems, including the heart, the kidneys, and the brain, we anticipate that studies in each of these organ systems should be encouraged with respect to the potential involvement of ACE2. Much interest has already been directed at the role of ACE2 with regard to the cardiovascular system with emphasis on the heart,13,14 although the relevance of ACE2 in terms of heart development and function in humans is still unclear. The role of ACE2 in kidney disease is already suggested by the finding that Ang-(1-7), a product of ACE2 activity, exerts a direct effect on renal hemodynamics.15 The role of ACE2 in the regulation of blood pressure, however, is a particularly promising avenue that must be further explored. Emphasis should be placed now on the role of ACE2 in hypertension and hypotension and the possibilities for treating or preventing the development of either one by modulating ACE2 expression and activity.
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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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