Pathophysiological role of angiotensin-converting enzyme in the cardiovascular system

Angiotensin I-converting enzyme (ACE, EC 3.4.15.1) is a zinc metallopeptidase involved in release of angiotensin II (Ang II) and inactivation of bradykinin (BK), two peptide hormones which play key roles in regulation of blood pressure, renal and cardiovascular functions. Ang II is an end-product of the highly regulated renin-angiotensin-aldosterone system (RAAS) while bradykinin is an end-product of the kallikrein-kinin system (KKS). Ang II is produced by the RAAS system from the precursor angiotensinogen, cleaved by the enzyme renin to angiotensin I (Ang I), and then cleaved by ACE to Ang II. Ang II is considered the most active agonist of this system, and its physiological actions are implemented through stimulation of specific receptors distributed widely throughout the body. Ang II is known to bind to the AT1 and AT2 binding site subtypes. Stimulation of the AT1 receptor results in a signaling pathway cascade in several cell types, leading to processes such as vasoconstriction, inflammation and cell proliferation. These are extremely important in many cardiovascular diseases, including hypertension, atherosclerosis and ventricular hypertrophy. The AT2 receptor is mainly expressed during the fetal stage and is only minimally expressed in adults under normal circumstances. Its role in the adult cardiovascular system remains unclear, but it apparently produces oppositional effects to the AT1 receptor. The existence of two active sites for ACE has generated speculation about their functional significance. In vitro these two domains display relatively broad substrate specificity, including cleavage of Ang I and BK. However, some biochemical features differentiate these active sites. ACE-specific inhibitors are one of the most widely prescribed drug classes in cardiology and are used for treatment of hypertension and heart failure. This overview discusses the pathophysiological role of ACE and its enzymatic products, principally Ang II.