Lysosomal cysteine peptidase cathepsin L protects against cardiac hypertrophy through blocking AKT/GSK3beta signaling.

Abstract	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/GSK3beta signaling cascade. Our in vitro studies further confirmed that CTSL expression in cardiomyocytes blunts cardiac hypertrophy through blocking of Akt/GSK3beta signaling. The study indicates that CTSL improves cardiac function and inhibits cardiac hypertrophy, inflammation, and fibrosis through blocking Akt/GSK3beta signaling.
Authors	Qizhu Tang, Jun Cai, Difei Shen, Zhouyan Bian, Ling Yan, You-Xin Wang, Jie Lan, Guo-Qing Zhuang, Wen-Zhan Ma, Wei Wang
Journal	Journal of molecular medicine (Berlin, Germany) (J Mol Med (Berl)) Vol. 87 Issue 3 Pg. 249-60 (Mar 2009) ISSN: 1432-1440 [Electronic] Germany
PMID	19096818 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Angiotensin II Atrial Natriuretic Factor GSK3B protein, human Glycogen Synthase Kinase 3 beta Gsk3b protein, mouse Gsk3b protein, rat Proto-Oncogene Proteins c-akt Glycogen Synthase Kinase 3 Cathepsins Caspases Cysteine Endopeptidases CTSL protein, human Cathepsin L Ctsl protein, mouse Ctsl protein, rat
Topics	Angiotensin II (pharmacology) Animals Animals, Newborn Apoptosis (genetics, physiology) Atrial Natriuretic Factor (genetics) Blotting, Western Cardiomegaly (genetics, metabolism, physiopathology) Caspases (metabolism) Cathepsin L Cathepsins (deficiency, genetics, metabolism) Cells, Cultured Cysteine Endopeptidases (deficiency, genetics, metabolism) Echocardiography (methods) Female Gene Expression (drug effects) Glycogen Synthase Kinase 3 (metabolism) Glycogen Synthase Kinase 3 beta Humans Male Mice Mice, Inbred C57BL Mice, Transgenic Myocardium (metabolism, pathology) Proto-Oncogene Proteins c-akt (metabolism) Rats Rats, Sprague-Dawley Reverse Transcriptase Polymerase Chain Reaction Signal Transduction (genetics, physiology)

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