Chymase as an Important Target for Preventing Complications of Metabolic Syndrome

S.      Takai; D.      Jin; M.      Miyazaki

doi:10.2174/092986710792232003

Abstract

Chymase plays a crucial role in angiotensin II formation in various tissues. Angiotensin II induces gene expressions of transforming growth factor (TGF)-β and matrix metalloproteinase (MMP)-9, and chymase also converts precursors of TGF-β and MMP-9 to their active forms. All of angiotensin II, TGF-β and MMP-9 are considered to be closely involved in the development and progression of metabolic syndrome and its complications. In a diabetic animal model, chymase induced pancreatic disorganization via attack of oxidative stress induced by augmentation of chymase-forming angiotensin II. In atherosclerotic lesions in patients, accumulation of chymase-positive cells was observed, and chymase inhibition prevented the development of atherosclerosis in an animal model. In Apo E-deficient mice, chymase inhibition prevents the development of angiotensin II-induced abdominal aneurysmal aorta (AAA). In this model, the AAA development on an increase in MMP-9 activities induced by angiotensin II, but the inhibition of MMP-9 activation by chymase inhibitor resulted in attenuation of the AAA development. Cardiac dysfunction after myocardial infarction was also attenuated by chymase inhibition. Steatosis and fiblosis in liver were strongly prevented by chymase inhibition in an animal model with nonalcoholic steatohepatitis which is involved in metabolic syndrome. Therefore, chymase inhibition may be useful for attenuating MMP-9 and TGF-β levels, in addition to reducing angiotensin II formation, and this function may provide powerful preventions of organ damages. In this review, we propose the significance of chymase as a target to prevent complications of metabolic syndrome.

Keywords: Angiotensin II, chymase, matrix metalloproteinase-9, metabolic syndrome, transforming growth factor-β

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