Cathepsin B deficiency attenuates cardiac remodeling in response to pressure overload via TNF-α/ASK1/JNK pathway

• Published in: American journal of physiology. Heart and circulatory physiology Vol. 308; no. 9; pp. H1143 - H1154
• Main Authors: Wu, Qing-Qing, Xu, Man, Yuan, Yuan, Li, Fang-Fang, Yang, Zheng, Liu, Yuan, Zhou, Meng-Qiao, Bian, Zhou-Yan, Deng, Wei, Gao, Lu, Li, Hongliang, Tang, Qi-Zhu
• Format: Journal Article
• Language: English
• Published: United States 01.05.2015
• Subjects: Animals; Apoptosis; Cathepsin B - antagonists & inhibitors; Cathepsin B - deficiency; Cathepsin B - genetics; Disease Models, Animal; Female; Fibrosis; HEK293 Cells; Humans; Hypertrophy, Left Ventricular - enzymology; Hypertrophy, Left Ventricular - genetics; Hypertrophy, Left Ventricular - pathology; Hypertrophy, Left Ventricular - physiopathology; Hypertrophy, Left Ventricular - prevention & control; JNK Mitogen-Activated Protein Kinases - antagonists & inhibitors; JNK Mitogen-Activated Protein Kinases - metabolism; Male; MAP Kinase Kinase Kinase 5 - metabolism; Mice, Knockout; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - enzymology; Myocytes, Cardiac - pathology; Protein Kinase Inhibitors - pharmacology; RNA Interference; Signal Transduction; Transfection; Tumor Necrosis Factor-alpha - metabolism; Ventricular Function, Left - drug effects; Ventricular Remodeling - drug effects; apoptosis; pressure overload; cathepsin B; cardiac remodeling
• ISSN: 0363-6135; 1522-1539
• DOI: 10.1152/ajpheart.00601.2014

Cathepsin B (CTSB), a member of the lysosomal cathepsin family that is expressed in both murine and human hearts, was previously shown to participate in apoptosis, autophagy, and the progression of certain types of cancers. Recently, CTSB has been linked to myocardial infarction. Given that cathepsin L, another member of the lysosomal cathepsin family, ameliorates pathological cardiac hypertrophy, we hypothesized that CTSB plays a role in pressure overload-induced cardiac remodeling. Here we report that CTSB was upregulated in cardiomyocytes in response to hypertrophic stimuli both in vivo and in vitro. Moreover, knockout of CTSB attenuated pressure overload-induced cardiac hypertrophy, fibrosis, dysfunction, and apoptosis. Furthermore, the aortic banding-induced activation of TNF-α, apoptosis signal-regulating kinase 1 (ASK1), c-Jun NH2-terminal kinases (JNK), c-Jun, and release of cytochrome c was blunted by CTSB deficiency, which was further confirmed in in vitro studies induced by angiotensin II. In cardiomyocytes pretreatment with SP600125, a JNK inhibitor, suppressed the cardiomyocytes hypertrophy by inhibiting the ASK1/JNK pathway. Altogether, these data indicate that the CTSB protein functions as a necessary modulator of hypertrophic response by regulating TNF-α/ASK1/JNK signaling pathway involved in cardiac remodeling.