Advances in biochemical and functional roles of angiotensin-converting enzyme 2 and angiotensin-(1-7) in regulation of cardiovascular function - PubMed (original) (raw)

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Advances in biochemical and functional roles of angiotensin-converting enzyme 2 and angiotensin-(1-7) in regulation of cardiovascular function

Carlos M Ferrario et al. Am J Physiol Heart Circ Physiol. 2005 Dec.

Abstract

Angiotensin-converting enzyme 2 (ACE2) is the first human homologue of ACE to be described. ACE2 is a type I integral membrane protein that functions as a carboxypeptidase, cleaving a single hydrophobic/basic residue from the COOH-terminus of its substrates. Because ACE2 efficiently hydrolyzes the potent vasoconstrictor angiotensin II to angiotensin (1-7), this has changed our overall perspective about the classical view of the renin angiotensin system in the regulation of hypertension and heart and renal function, because it represents the first example of a feedforward mechanism directed toward mitigation of the actions of angiotensin II. This paper reviews the new data regarding the biochemistry of angiotensin-(1-7)-forming enzymes and discusses key findings such as the elucidation of the regulatory mechanisms participating in the expression of ACE2 and angiotensin-(1-7) in the control of the circulation.

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Figures

Fig. 1.

Fig. 1.

Current view of renin angiotensin system enzymes and peptides. ACE, angiotensin-converting enzyme; ACE2, angiotensin-converting enzyme 2; EPs, endopeptidases (neprilysin, prolyl endopeptidase 24.26, and metalol protease 24.15) (109) controlling tissue-specific production of angiotensin-(1–7) [ANG-(1–7)] from ANG I [ANG-(1–10)]; ANG receptors are AT1-R, AT2-R, and AT1–7-R, [type 1, type 2, and ANG-(1–7) receptor subtypes, respectively] and insulin-regulated aminopeptidase (IRAP) (84). Nomenclature for ANG peptides follows the recommendations of the Nomenclature Committee for the Council for High Blood Pressure Research (13) as the following: angiotensin II [angiotensin-(1–8)]; angiotensin III [angiotensin-(2–8)]; angiotensin IV [angiotensin-(3–8)]. Call outs denote additional enzymatic cleavage activity of the angiotensins-forming enzymes.

Fig. 2.

Fig. 2.

Schematic representation of feedforward enzymatic pathway through which ANG II is cleaved from ANG I by ACE and then further catalyzed by ACE2 into ANG-(1–7). In turn, ANG-(1–7) is metabolized by ACE into the ANG fragment ANG-(1–5).

Fig. 3.

Fig. 3.

Representative outline of changes induced by ACE inhibitors (ACEI) or ANG II type 1 receptor blockers (ARBs). Other abbreviations as in Fig. 1.

Fig. 4.

Fig. 4.

Conscious instrumented spontaneously hypertensive rats and [mRen2]27 transgenic hypertensive rats exposed to either a normal (0.5%) or a low (0.05%) -salt diet regimen for 12 days were administered systemic doses of either an affinity purified ANG-(1–7) antibody or the selective ANG-(1–7) receptor antagonist [(

d

-Ala7)-ANG-(1–7)]. Both endogenous neutralization of ANG-(1–7) and blockade of AT-1–7 receptors are associated with dose-dependent increases in the mean arterial pressure (MAP) of salt-depleted rats confirming a buffering role of the heptapeptide in which the condition of salt depletion causes increases in plasma renin activity and ANG II. Adapted from Iyer et al. (53).

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