New Approaches to Blockade of the Renin–Angiotensin–Aldosterone System: Chymase as an Important Target to Prevent Organ Damage

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Chymase plays a crucial role in angiotensin II formation in various tissues. Angiotensin II induces gene expression of transforming growth factor (TGF)-β and matrix metalloproteinase (MMP)-9 precursors, and chymase can convert precursors of TGF-β and MMP-9 to their active forms. In cultured fibroblasts, significant increases in cell growth and TGF-β 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-β 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-β 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.