The Role for Cysteine Protease Cathepsin in Left Ventricular Remodeling and Gene Therapy Application.

背景：组织蛋白酶的激活在几种疾病状态下促进组织重塑。本研究测试的假设，组织蛋白酶抑制防止左心室重塑和功能障碍的发展，CHF与hypertension.Methods和结果：达尔盐敏感大鼠喂食8%NaCl饮食从7周的年龄作为CHF模型任意分配到三个治疗组在12周。组织蛋白酶mRNA和蛋白质的丰度定位于心肌细胞（CMC）和组织蛋白酶依赖性活动的增加，在CHF大鼠的左心室，并通过奥美沙坦治疗减少。奥美沙坦可抑制CHF大鼠冠状动脉内平滑肌细胞（SMC）中弹性膜降解，同时降低局部组织蛋白酶S表达，并恢复弹性蛋白与胶原的比例。此外，奥美沙坦不仅抑制CHF大鼠白细胞介素-1 β表达和巨噬细胞浸润，而且抑制NADPH氧化酶组分（p22^<phox>、gp 91 ^<phox>和p47^<phox>）的水平，同时降低NADPH活性和O_2^-产生。这些伴随着心脏纤维化、僵硬和功能障碍的改善。有趣的是，E64 d观察到所有这些改善。抗氧化剂MnTmPyp和N-乙酰半胱氨酸抑制H2 O2诱导的增加组织蛋白酶的表达和弹性蛋白溶解活性在文化CMCs和SMC.Conclusions：这些结果表明，组织蛋白酶可能会触发和促进LV重塑，和奥美沙坦介导的抑制血管紧张素1型受体抑制组织蛋白酶通过抑制炎症和氧化应激，导致心脏重塑和功能障碍的预防。

Background : Cathepsin activation contributes to tissue remodeling in several disease states. The present study tested the hypothesis that cathepsin inhibition prevents LV remodeling and dysfunction in the development of CHF associated with hypertension.Methods and Results : Dahl salt-sensitive rats fed an 8% NaCl diet from age 7 weeks served as a CHF model arbitrarily assigned to three treatment groups at age 12 weeks. The abundance of cathepsin mRNAs and proteins localized in cardiac myocytes (CMCs) and cathepsin-dependent activities were increased in the left ventricle of CHF rats, and were reduced by olmesartan treatment. Olmesartan suppressed the elastic lamina degradation concomitant with decreased local cathepsin S expression in intracoronary smooth muscle cells (SMCs) and restored the ratio of elastin to collagen in CHF rats. Furthermore, olmesartan suppressed not only interleukin-1β expression and macrophage infiltration but also levels of NADPH oxidase components (p22^<phox>, gp91^<phox>, and p47^<phox>) concomitant with decreased NADPH activity and O_2^- production in CHF rats. These were accompanied by improved cardiac fibrosis, stiffness, and dysfunction. Interestingly, all of these improvements were observed by E64d. The antioxidants MnTmPyp and N-acetylcysteine inhibited the H2O2-induced increase in cathepsin expression and elastolytic activity in culture CMCs and SMC.Conclusions : These results suggest that cathepsins are likely to trigger and promote LV remodeling, and that olmesartan-mediated inhibition of angiotensin type1 receptor inhibits cathepsins by suppressing inflammation and oxidative stress, leading to the prevention of cardiac remodeling and dysfunction.