The chymase-angiotensin system in humans: biochemistry, molecular biology and potential role in cardiovascular diseases.
Angiotensin I-converting enzyme (ACE) inhibitors are highly effective in the treatment of cardiovascular diseases. However, the relationship among the antihypertensive effects of ACE inhibitors, ACE inhibition and plasma angiotensin II levels is complex. During chronic therapy with ACE inhibition, plasma angiotensin II levels return to normal despite a continued antihypertensive effect. Recent studies show that a conversion of angiotensin I to angiotensin II in tissues can proceed despite complete ACE inhibition. In the search for a potential ACE inhibitor-resistant angiotensin II-forming enzyme activity in human heart tissue, chymase was identified as a major angiotensin II-forming enzyme. In primates, chymase-like angiotensin II-forming activity is localized in a number of tissues including the heart, blood vessels and lungs. Within the human heart, mast cells and endothelial cells are the sites of synthesis and storage of chymase, but a high level of the secreted chymase is also found in the cardiac interstitium, associated with the extracellular matrix. Mammalian chymases may be divided into two distinct structural groups, alpha and beta. alpha-chymases, such as human chymase, are highly specific and efficient angiotensin II-forming enzymes. beta-chymases, including several rat and mouse chymases, have a broad substrate specificity like chymotrypsin and do not form angiotensin II. In humans and baboons only a single chm gene of the alpha-subtype can be identified. By using an angiotensin I analogue that is selectively converted to angiotensin II by chymase and not ACE, a functional chymase-dependent angiotensin II formation has recently been demonstrated in conscious baboons.(ABSTRACT TRUNCATED AT 250 WORDS)
Liao
Y
Y
Department of Molecular Cardiology, Cleveland Clinic Foundation, Ohio 44195-5069, USA.
Husain
A
A
D000803:Angiotensin I / Q000378:metabolism*; D000804:Angiotensin II / Q000097:blood; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D000959:Antihypertensive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002318:Cardiovascular Diseases / Q000188:drug therapy* / Q000201:enzymology; D053818:Chymases; D006331:Heart Diseases / Q000188:drug therapy* / Q000201:enzymology; D006801:Humans; D006973:Hypertension / Q000188:drug therapy*; D008967:Molecular Biology; D012697:Serine Endopeptidases / Q000378:metabolism*
D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D000804:Angiotensin II; D000803:Angiotensin I; D012697:Serine Endopeptidases; D053818:Chymases