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

背景：组织蛋白酶的激活有助于多种疾病状态下的组织重塑。本研究验证了组织蛋白酶抑制在高血压相关的CHF发展过程中阻止左室重构和功能障碍的假设。方法与结果：从7周龄开始饲喂8% NaCl的Dahl盐敏感大鼠作为CHF模型，12周龄时随机分为3个治疗组。心肌细胞（CMCs）组织蛋白酶mrna和蛋白的丰度和组织蛋白酶依赖活性在CHF大鼠左心室增加，奥美沙坦治疗降低。奥尔美沙坦抑制CHF大鼠冠状动脉内平滑肌细胞（SMCs）弹性层降解并降低局部组织蛋白酶S表达，恢复弹性蛋白与胶原的比值。此外，奥美沙坦不仅抑制了白细胞介素-1β的表达和巨噬细胞的浸润，还抑制了NADPH氧化酶组分（p22^<phox>, gp91^<phox>和p47^<phox>）的水平，同时降低了CHF大鼠的NADPH活性和O_2^-的产生。同时伴有心肌纤维化、僵硬和功能障碍的改善。有趣的是，所有这些改进都被E64d观察到。抗氧化剂MnTmPyp和n -乙酰半胱氨酸抑制h2o2诱导的培养cmc和SMC组织蛋白酶表达和弹性分解活性的增加。结论：这些结果提示，组织蛋白酶可能触发和促进左室重构，奥美沙坦介导的血管紧张素1型受体抑制通过抑制炎症和氧化应激抑制组织蛋白酶，从而预防心脏重构和功能障碍。

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.