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)-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. © 2010 the japanese pharmacological society.