New approaches to blockade of the renin-angiotensin-aldosterone system: chymase as an important target to prevent organ damage.
Chymase plays a crucial role in angiotensin II formation in various tissues. Angiotensin II induces gene expression of transforming growth factor (TGF)-beta and matrix metalloproteinase (MMP)-9 precursors, and chymase can convert precursors of TGF-beta and MMP-9 to their active forms. In cultured fibroblasts, significant increases in cell growth and TGF-beta levels were observed after chymase injection; these increases were inhibited by a chymase inhibitor, but not by an angiotensin II-receptor blocker. In apolipoprotein E-deficient mice, abdominal aortic aneurysm (AAA) development depends on an increase in MMP-9 activities induced by angiotensin II infusion, but the inhibition of MMP-9 activation by a chymase inhibitor resulted in attenuation of the angiotensin II-induced AAA development. The upregulation of MMP-9 and TGF-beta levels is involved in damage to various organs, but these gene expressions are not completely induced by angiotensin II alone. Therefore, chymase inhibition may be useful for attenuating MMP-9 and TGF-beta levels, in addition to reducing angiotensin II formation, and this function may provide powerful organ protection. In this review, we propose the possible use of chymase inhibitors as agents to prevent organ damage.
Takai
Shinji
S
Department of Pharmacology, Osaka Medical College, Takatsuki City, Japan. pha010@art.osaka-med.ac.jp
Jin
Denan
D
Miyazaki
Mizuo
M
D000818:Animals; D049109:Cell Proliferation; D053818:Chymases / Q000037:antagonists & inhibitors*; D004730:Endothelium, Vascular / Q000166:cytology; D004789:Enzyme Activation; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D012084:Renin-Angiotensin System / Q000187:drug effects*; D016212:Transforming Growth Factor beta / Q000378:metabolism
D016212:Transforming Growth Factor beta; D053818:Chymases; D020780:Matrix Metalloproteinase 9