And Receptors

The actions of the RAS are regulated both by angiotensinases in the extracellular milieu and by angiotensin receptor-coupled signaling networks. The precursor for angio-

From: Contemporary Cardiology: Diabetes and Cardiovascular Disease, Second Edition Edited by: M. T. Johnstone and A. Veves © Humana Press Inc., Totowa, NJ

Aminopeptidase Angiotensin Cathepsin

Fig. 1. Overview of the renin-angiotensin system. Angiotensinogen and angiotensin I-derived peptides are cleaved via a number of extracellular proteases resulting in at least four biologically active peptides, including Ang II, angiotensin II Asp1-Phe8, Ang III, Angiotensin Arg2-Phe8; Ang IV, Angiotensin Val3-Phe8; and Ang1-7, Angiotensin Asp1-Pro7. Angiotensin-converting enzyme 1 (ACE) generates Ang II and is the target of ACE inhibitors. ACE2 generates Ang1-9, Angiotensin Asp1-His9, which is further cleaved by ACE1 to generate Ang1-7. Angiotensin receptor blockers (ARBs) inhibit Ang II and Ang III signaling via the AT1 receptor.

Fig. 1. Overview of the renin-angiotensin system. Angiotensinogen and angiotensin I-derived peptides are cleaved via a number of extracellular proteases resulting in at least four biologically active peptides, including Ang II, angiotensin II Asp1-Phe8, Ang III, Angiotensin Arg2-Phe8; Ang IV, Angiotensin Val3-Phe8; and Ang1-7, Angiotensin Asp1-Pro7. Angiotensin-converting enzyme 1 (ACE) generates Ang II and is the target of ACE inhibitors. ACE2 generates Ang1-9, Angiotensin Asp1-His9, which is further cleaved by ACE1 to generate Ang1-7. Angiotensin receptor blockers (ARBs) inhibit Ang II and Ang III signaling via the AT1 receptor.

tensin-derived peptides is angiotensinogen (AGT), a 452 amino acid protein in the serpin family that undergoes N-terminal proteolysis by renin to generate the decapeptide angiotensin I (Ang I) and des(Ang I)AGT (Fig. 1). Cathepsin G and cathepsin D also have renin-like activities, which may contribute substantially to Ang I production by vascular smooth muscle cells (VSMC) (19). Once formed, Ang I is cleaved by ACE-1 (dipeptidyl carboxypeptidase 1), chymase, or cathepsin G to produce the octapeptide Ang II, which activates both angiotensin ATI and AT2 receptor isotypes (20-23). The relative contributions of ACE and alternative Ang I-processing pathways to Ang II generation appear to vary among specific tissues, and among species (22). In the human heart in vivo, ACE appears to account for the majority of Ang II production (24). Atherosclerotic plaques contain both ACE and chymase activity (25-27), suggesting that both pathways contribute to local Ang II generation within vascular lesions. Ang I can also be cleaved by the carboxypeptidase ACE-2 to generate Ang 1-9 (28), which results in decreased Ang II

production. Targeted disruption of ACE-2 in mice results in elevated levels of Ang II and severe cardiac contractile dysfunction (29). Thus, ACE-1 and ACE-2 appear to compete for Ang I substrate, such that ACE-2 diverts available angiotensin peptide away from the Ang II/AT1 pathway.

Ang II and Ang1-9 can undergo further proteolytic processing to generate additional biologically active peptides (Fig. 1). Conversion of Ang II to angiotensin Arg2-Phe8 (Ang III) occurs primarily via aminopeptidase A with Ang III retaining its ability to activate the AT1 receptor (30,31). Ang III is a major effector peptide of the RAS in the brain in which it exerts neuronal effects on BP control (32). Aminopeptidase or endopep-tidase cleavage of Ang II can also generate angiotensin Val3-Phe8 (Ang IV), which appears to activate endothelial nitric oxide synthase (eNOS) activity and thereby increases blood flow (33,34). Ang IV has been reported to bind insulin-regulated aminopeptidase, which may indirectly affect neuropeptide half-life (35), however, a role of the AT1 receptor in mediating Ang IV action has also been reported (36). C-terminal processing of Ang II by prolylcarboxypeptidase (angiotensinase C) or cleavage of Ang1-9 by ACE-1 generates angiotensin Asp1-Pro7 (Ang1-7) (37), which binds the G protein-coupled Mas receptor and elicits inhibitory effects on VSMC growth and antihypertensive effects (38-40).

Within the RAS, the AT1 receptor appears to mediate most of Ang II's growth promoting, metabolic, and gene-regulatory actions (41,42). The phenotype of AT1 gene-deficient mice is virtually identical to that of angiotensinogen-deficient mice (43,44) and the pressor response to Ang II infusion is abolished in AT1 receptor null mice (43). However, although Ang II is the major agonist for the AT1 receptor there is evidence that Ang III, Ang IV, and mechanical stress can also activate this receptor pathway (31,36,45).

Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

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