Does the angiotensin-converting enzyme (ACE)/ACE2 balance contribute to the fate of angiotensin peptides in programmed hypertension?

The renin-angiotensin system (RAS) plays a key role in blood pressure regulation, fluid and electrolyte balance, cellular growth, thirst, and cardiac/renal function. The classic system primarily involves 2 enzymes: renin, which cleaves angiotensinogen to the inactive decapeptide angiotensin (Ang) I; and Ang-converting enzyme (ACE), a dipeptidyl carboxypeptidase that hydrolyzes Ang I to the octapeptide Ang II. The elucidation of the ACE pathway in parallel with potent and selective ACE inhibitors is clearly a pivotal achievement in our understanding of the RAS and in attaining effective therapies for hypertension and end organ damage. Indeed, ACE inhibitors attenuate Ang II formation and augment the levels of the heptapeptide Ang (1–7), a peptide that counterbalances the actions of Ang II on blood pressure and cellular growth through a unique receptor system. Ang II mediates the majority of its actions at the Ang II type 1 (AT1) receptor, including the stimulation of vasoconstriction, sodium retention, cellular growth, and oxidative stress, whereas recent studies show that Ang (1–7) at the AT1–7 or mas receptor and Ang II via the AT2 receptor subtype counterregulate the actions of Ang II at the AT1 receptor. The discovery of the ACE homolog ACE2 provides further evidence that the RAS is far more complex than originally thought. The enzymatic cascade of the RAS should now encompass the ACE2-dependent pathways that directly yield Ang (1–9) from Ang I and degrade Ang II to Ang (1–7) (Figure). The interplay between ACE and ACE2 that may govern the formation and metabolism of Ang effector peptides warrants the simultaneous study of both enzymes to ultimately assess their contribution to blood pressure regulation and cardiac/renal function. ACE is a zinc metalloendopeptidase that functions as a C-terminal peptidyl dipeptidase and acts to convert Ang I to Ang II and inactivate the vasodilator bradykinin. The 2 forms of ACE, somatic and testicular, are encoded from a single gene. Somatic ACE is highly expressed in the vascular endothelial cells and is produced by other cell types, including macrophages, tubular epithelium, and gut epithelium. Somatic ACE has 2 independent catalytic sites with distinct properties, and it exists as soluble and membrane-bound forms. The germinal form, which is found exclusively in the testes, has 1 catalytic site and is involved in fertility. Recently, it has been shown that ACE hydrolyzes Ang (1–7) to Ang (1–5), thus facilitating the breakdown of Ang (1–7).1,2 Under conditions of ACE inhibition, not only is there an increase in the substrate Ang I, which can be converted to Ang (1–7) through the action of endopeptidases such as neprilysin and prolylendopeptidase, but there is also prevention of the breakdown of Ang (1–7). Acting at multiple sites in the processing scheme, ACE inhibition results in increased plasma, tissue, and urine levels of Ang (1–7).3–6 Blockade of Ang (1–7) by its specific receptor antagonist D-alanine7-Ang (1–7) reverses the blood pressure–lowering actions of ACE inhibitor lisinopril,7 illustrating that the increased levels of Ang (1–7) account for a part of the antihypertensive actions of ACE inhibition. ACE2 is the first known human homologue of ACE, which was isolated from 2 human cDNA libraries prepared from ventricular and lymphoma tissues.8,9 The enzyme exhibits 42% sequence identity and 61% sequence similarity to ACE. ACE2 contains a single zinc-binding domain HEXXH, which is homologous to the active sites of ACE; however, it is not inhibited by ACE inhibitors.10 ACE2 exhibits carboxypeptidase activity cleaving a single amino acid residue at the carboxyl terminus. Although ACE2 was first shown to hydrolyze Ang I to release Ang (1–9) with subsequent hydrolysis by ACE to Ang (1–7) in cardiomyocytes, the kinetic data by Vickers et al11 with recombinant ACE2 revealed a relatively low catalytic constant (kcat) for Ang (1–9) formation. In contrast, the hydrolysis of Ang II to Ang (1–7) by ACE2 exhibited a very high catalytic efficiency (kcat/Km), 400-fold greater than that for Ang I to Ang (1–9). In this scheme, the formation of the vasodilator peptide Ang (1–7) occurs at the expense of the vasoconstrictor hormone Ang II. Despite the kinetic data favoring Ang II as the substrate for ACE2, Li et al12 found that Ang I was the preferred substrate for ACE2 in proximal tubules with no evidence for ACE2-dependent generation of Ang (1–7) from Ang II. These data emphasize that both Ang I and Ang II should be used as substrates to characterize ACE2 activity. In the current issue of Hypertension, Rivière et al13 provide an important study by examining the regulation and distribution of ACE2 mRNA and ACE mRNA in a rat model of fetal programming. In their study, adult offspring (4 months old) (FR30) of dams food-restricted throughout gestation showed mild hypertension, reduced nephron number, and elevated The opinions expressed in this editorial commentary are not necessarily those of the editors or of the American Heart Association. From the Hypertension and Vascular Disease Center, Wake Forest University School of Medicine, Winston-Salem, NC Correspondence to K. Bridget Brosnihan, Hypertension and Vascular Disease Center, Wake Forest University School of Medicine, Medical Center Blvd, Winston-Salem, NC. E-mail [email protected] (Hypertension. 2005;46:1097-1099.) © 2005 American Heart Association, Inc.