Superoxide-dependent cathepsin activation is associated with hypertensive myocardial remodeling and represents a target for angiotensin II type 1 receptor blocker treatment
Superoxide-dependent cathepsin activation is associated with hypertensive myocardial remodeling and represents a target for angiotensin II type 1 receptor blocker treatment
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DOI：
10.2353/ajpath.2008.071126
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发表时间：
2008-08-01
影响因子：
6
通讯作者：
Yokota, Mitsuhiro
中科院分区：
文献类型：
--
作者：
Cheng, Xian Wu;Murohara, Toyoaki;Yokota, Mitsuhiro
心肌组织蛋白的弹性溶解活性与高血压性心力衰竭(HF)有关。鉴于在高血压性心衰的发展过程中，活性氧也参与了与心脏重构相关的蛋白酶激活，我们研究了活性氧诱导的组织蛋白酶激活系统在心脏重构中的作用。将12~19周龄的Dahl盐敏感型高血压大鼠分为3组，分别用溶媒、组织蛋白酶抑制剂E64d或血管紧张素受体阻滞剂奥美沙坦治疗。心衰大鼠左心室组织蛋白酶表达和活性增加，奥美沙坦可抑制这种作用，恢复左心室弹性蛋白和胶原的平衡，抑制心衰大鼠冠状动脉弹性膜的降解。此外，奥美沙坦还可抑制NADPH氧化酶亚基和活性的上调以及超氧化物的产生。奥美沙坦的这些作用与E64d相似，并伴随着心脏纤维化的改善。最后，奥美沙坦和apocynin可降低血管紧张素H诱导的新生大鼠心肌细胞组织蛋白酶mRNA和蛋白水平的升高。这些数据表明，组织蛋白酶可能触发和促进心脏重塑，阻断血管紧张素H 1型受体通过抑制NADPH氧化酶产生超氧化物来减弱组织蛋白酶的表达和活性，从而减轻心脏重塑和功能障碍。
The elastolytic activity of cathepsins in the myocardium is implicated in hypertensive heart failure (HF). Given that reactive oxygen species are also implicated in protease activation associated with cardiac remodeling, we examined the role of the reactive oxygen species-induced cathepsin activation system in cardiac remodeling during the development of hypertensive HF. Dahl salt-sensitive hypertensive rats maintained on a high-salt diet were treated with vehicle, the cathepsin inhibitor E64d, or the angiotensin receptor blocker olmesartan from 12 to 19 weeks of age. Cathepsin expression and activity were increased in the left ventricle of HF rats; olmesartan inhibited these effects, restored the balance between elastin and collagen in the left ventricle, and suppressed degradation of the elastic lamina of coronary arteries of HF rats. Furthermore, olmesartan inhibited up-regulation of NADPH oxidase subunits and activity as well as superoxide generation. These effects of olmesartan were mimicked by E64d and were accompanied by amelioration of cardiac fibrosis. Finally, olmesartan and apocynin reduced angiotensin H-induced increases in cathepsin mRNA and protein levels in cultured rat neonatal cardiac myocytes. These data suggest that cathepsins likely trigger and promote cardiac remodeling and that blocking the angiotensin H type 1 receptor attenuates cathepsin expression and activity by inhibiting the production of superoxide by NADPH oxidase, thereby attenuating cardiac remodeling and dysfunction.