Cardiac chymase: pathophysiological role and therapeutic potential of chymase inhibitors.
On release from cardiac mast cells, alpha-chymase converts angiotensin I (Ang I) to Ang II. In addition to Ang II formation, alpha-chymase is capable of activating TGF-beta1 and IL-1beta, forming endothelins consisting of 31 amino acids, degrading endothelin-1, altering lipid metabolism, and degrading the extracellular matrix. Under physiological conditions the role of chymase in the mast cells of the heart is uncertain. In pathological situations, chymase may be secreted and have important effects on the heart. Thus, in animal models of cardiomyopathy, pressure overload, and myocardial infarction, there are increases in both chymase mRNA levels and chymase activity in the heart. In human diseased heart homogenates, alterations in chymase activity have also been reported. These findings have raised the possibility that inhibition of chymase may have a role in the therapy of cardiac disease. The selective chymase inhibitors developed to date include TY-51076, SUN-C8257, BCEAB, NK320, and TEI-E548. These have yet to be tested in humans, but promising results have been obtained in animal models of myocardial infarction, cardiomyopathy, and tachycardia-induced heart failure. It seems likely that orally active inhibitors of chymase could have a place in the treatment of cardiac diseases where injury-induced mast cell degranulation contributes to the pathology.
Doggrell
Sheila A
SA
School of Biomedical Sciences, The University of Queensland, Australia. s_doggrell@yahoo.com
Wanstall
Janet C
JC
D000818:Animals; D053818:Chymases; D006331:Heart Diseases / Q000188:drug therapy / Q000201:enzymology*; D006801:Humans; D009206:Myocardium / Q000201:enzymology*; D012697:Serine Endopeptidases / Q000502:physiology*; D015842:Serine Proteinase Inhibitors / Q000627:therapeutic use
D015842:Serine Proteinase Inhibitors; D012697:Serine Endopeptidases; D053818:Chymases