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

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.

Effects of ACE-Inhibitors and Angiotensin Receptor Blockers on Inflammation

“…Most of the known pressor, proliferative, and profibrotic actions of angiotensin II are mediated through its binding to the angiotensin type 1 (AT1) receptor. After the conversion of angiotensinogen to angiotensin I (Ang I) in the circulation and tissues, Ang I, through the interaction with angiotensin-converting enzyme (ACE) forms angiotensin II, whereas additional angiotensin peptides, such as angiotensin-(1-7), are generated from either angiotensin I by the action of several tissue endopeptidases or the metabolism of angiotensin II by ACE-2, a newly recognized ACE homologue [46]; the ACE and the ACE2 systems will be better elucidated in the next part of this review.…”

“…For example, Ang-(1-7), a heptapeptide fragment of Ang II, can be formed from Ang I or Ang II by the actions of several endopeptidases or from Ang II by the action of carboxypeptidases, including one with significant structural homology to ACE (which has been termed "ACE 2"). Unlike ACE, this enzyme does not convert Ang I to Ang II and its activity and Ang-(1-7) levels are not affected by ACE inhibitors (ACEIs) and ARBs [46,80].…”

“…Ang-(1-7), which seems to act via a unique receptor, was first described to have vasodilatory effects and act as a natural ACEi, acting as a modulator of the RAAS [46,81]. So, ACE2 activity and Ang-(1-7) may counterbalance the activity of the ACE-mediated way, whose blockage is actually a therapeutical target.…”

Angiotensin‐(1‐7): Pharmacology and New Perspectives in Cardiovascular Treatments

“…1] by our laboratory in 1988 (Schiavone et al 1988) and the cloning of ACE2 in 2000 (Donoghue et al 2000;Tipuis et al 2000) have led to a new perception of the intrinsic mechanisms through which the RAS regulates homeostasis. Ang-(1-7) is a downstream heptapeptide product of the system that can regulate blood pressure (Benter et al 1995b;Ferrario et al 2005), cardiac function (Ferreira et al 2002;Loot et al 2002;De Mello et al 2004), and cell growth (Tallant et al 2005).…”

Gradual reactivation of vascular angiotensin I to angiotensin II conversion during chronic ACE inhibitor therapy in patients with diabetes mellitus

“…To date, there are no data on this mechanistic question in non-CHF patients. Recent new insights in angiotensin research do not offer any simple alternative explanations for our finding [12]. For example, AI accumulates during ACE inhibitor therapy and some of that becomes the vasodilator, angiotensin (1-7), but there is no apparent reason why less AI should become angiotensin (1-7) during chronic ACE inhibitor therapy, unless more AI is channelled into AII instead, which is what we are proposing anyway.…”