Lysosomal cysteine peptidase cathepsin L protects against cardiac hypertrophy through blocking AKT/GSK3β signaling
Lysosomal cysteine peptidase cathepsin L protects against cardiac hypertrophy through blocking AKT/GSK3β signaling
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DOI：
10.1007/s00109-008-0423-2
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发表时间：
2009-03-01
影响因子：
4.7
通讯作者：
Wang, Wei
中科院分区：
文献类型：
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作者：
Tang, Qizhu;Cai, Jun;Wang, Wei
溶酶体半胱氨酸肽酶组织蛋白酶L（CTSL）是一种重要的溶酶体蛋白酶，参与多种细胞功能，包括细胞内蛋白质周转、表皮稳态和毛发发育。小鼠CTSL缺乏导致进行性扩张型心肌病。在本研究中，我们测试了小鼠心脏中人CTSL的心脏过表达将在体内防止心脏肥大的假设。使用体外和体内模型研究了组成型人CTSL表达对心脏肥大的影响。在CTSL转基因小鼠和对照动物中通过主动脉结扎（AB）产生心脏肥大。心脏肥大的程度通过二维和M型超声心动图以及心脏样本的分子和病理分析来定量。人CTSL在鼠心脏中的组成性过表达减弱了肥大反应，显著减少了细胞凋亡和纤维化。在对肥大刺激作出反应的CTSL水平增加的心脏中，心脏功能也得到了保护。这些有益作用与Akt/GSK 3 β信号级联的衰减相关。我们的体外研究进一步证实，心肌细胞中的CTSL表达通过阻断Akt/GSK 3 β信号传导来减弱心脏肥大。该研究表明，CTSL通过阻断Akt/GSK 3 β信号传导改善心脏功能并抑制心脏肥大，炎症和纤维化。
The lysosomal cysteine peptidase cathepsin L (CTSL) is an important lysosomal proteinase involved in a variety of cellular functions including intracellular protein turnover, epidermal homeostasis, and hair development. Deficiency of CTSL in mice results in a progressive dilated cardiomyopathy. In the present study, we tested the hypothesis that cardiac overexpression of human CTSL in the murine heart would protect against cardiac hypertrophy in vivo. The effects of constitutive human CTSL expression on cardiac hypertrophy were investigated using in vitro and in vivo models. Cardiac hypertrophy was produced by aortic banding (AB) in CTSL transgenic mice and control animals. The extent of cardiac hypertrophy was quantitated by two-dimensional and M-mode echocardiography as well as by molecular and pathological analyses of heart samples. Constitutive overexpression of human CTSL in the murine heart attenuated the hypertrophic response, markedly reduced apoptosis, and fibrosis. Cardiac function was also preserved in hearts with increased CTSL levels in response to hypertrophic stimuli. These beneficial effects were associated with attenuation of the Akt/GSK3 beta signaling cascade. Our in vitro studies further confirmed that CTSL expression in cardiomyocytes blunts cardiac hypertrophy through blocking of Akt/GSK3 beta signaling. The study indicates that CTSL improves cardiac function and inhibits cardiac hypertrophy, inflammation, and fibrosis through blocking Akt/GSK3 beta signaling.