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Lysosomal cysteine peptidase cathepsin L protects against cardiac hypertrophy through blocking AKT/GSK3β signaling

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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/GSK3β signaling cascade. Our in vitro studies further confirmed that CTSL expression in cardiomyocytes blunts cardiac hypertrophy through blocking of Akt/GSK3β signaling. The study indicates that CTSL improves cardiac function and inhibits cardiac hypertrophy, inflammation, and fibrosis through blocking Akt/GSK3β signaling.

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Sources of funding

National Natural Science Foundation of China (30771193), Research Fund for the Doctoral Program of Higher Education of China (no. 20050025002) and Beijing Natural Science Foundation (5072007) to Wei Wang. National Natural Science Foundation of China (30670216), Research Fund for the Doctoral Program of Higher Education of China (no. 2007042086103) to Qizhu Tang.

Conflict of interests

None declared.

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Authors and Affiliations

  1. Cardiovascular Research Institute of Wuhan University and Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060, People’s Republic of China

    Qizhu Tang, Difei Shen, Zhouyan Bian & Ling Yan

  2. Cardiovascular Research Center, Massachusettes General Hospital, Harvard Medical School, Charlestown, MA, 02129, USA

    Jun Cai

  3. Department of Cardiology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, 100020, People’s Republic of China

    Jun Cai

  4. Graduate School of Chinese Academy of Sciences, Beijing, 100049, People’s Republic of China

    You-Xin Wang, Jie Lan, Guo-Qing Zhuang, Wen-Zhan Ma & Wei Wang

  5. School of Public Health and Family Medicine, Capital Medical University, Beijing, 100069, People’s Republic of China

    You-Xin Wang, Jie Lan, Guo-Qing Zhuang, Wen-Zhan Ma & Wei Wang

Authors
  1. Qizhu Tang
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  2. Jun Cai
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  3. Difei Shen
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  4. Zhouyan Bian
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  5. Ling Yan
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  6. You-Xin Wang
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  7. Jie Lan
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  8. Guo-Qing Zhuang
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  9. Wen-Zhan Ma
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  10. Wei Wang
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Correspondence to Qizhu Tang.

Additional information

Qizhu Tang, Jun Cai and Wei Wang contributed equally to this work.

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Tang, Q., Cai, J., Shen, D. et al. Lysosomal cysteine peptidase cathepsin L protects against cardiac hypertrophy through blocking AKT/GSK3β signaling. J Mol Med 87, 249–260 (2009). https://doi.org/10.1007/s00109-008-0423-2

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  • DOI: https://doi.org/10.1007/s00109-008-0423-2

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