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Expression of active protein phosphatase 1 inhibitor-1 attenuates chronic beta-agonist-induced cardiac apoptosis

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Abstract

Cardiac apoptosis has been considered an important contributing factor to heart failure. Several subcellular mechanisms, including increased protein phosphatase 1 activity, have been suggested to induce apoptosis. Protein phosphatase 1 is regulated by an endogenous inhibitor-1 (I-1) that is activated upon phosphorylation at threonine 35 via protein kinase A. Here, we tested whether cardiac-specific overexpression of a constitutively active (T35D, AA 1-65) inhibitor-1 (I-1c), could also affect cardiac apoptosis and heart failure progression induced by prolonged β-adrenergic stimulation. We found that either acute or chronic expression of I-1c reduced isoproterenol (ISO)-induced apoptosis assessed by nuclear condensation, TUNEL staining and DNA fragmentation. The beneficial effects of I-1c were associated with increased expression of the anti-apoptotic protein Bcl-2, decreased expression of the pro-apoptotic protein Bax and reduced levels of active caspases as well as increased activation of ERK. These findings suggest that mitochondrial signaling and ERK activation may be involved in the I-1c cardioprotective effects against apoptosis induced by prolonged β-adrenergic stimulation.

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Acknowledgments

This work was supported by NIH grants HL-26507, HL-64018, and HL-77101, the Leducq Foundation (to E.G. Kranias), NIH grant HL-087861 (to G.C. Fan) and an AHA postdoctoral fellowship 0525435B (to G. Chen).

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Authors and Affiliations

  1. Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH, 45267-0575, USA

    Guoli Chen, Xiaoyang Zhou, Stela Florea, Jiang Qian, Wenfeng Cai, Zhiguo Zhang, Guo-Chang Fan & Evangelia G. Kranias

  2. Foundation for Biomedical Research of the Academy of Athens, 11527, Athens, Greece

    Evangelia G. Kranias

  3. Department of Cardiology, Renming Hospital of Wuhan University, Wuhan, 430060, China

    Xiaoyang Zhou

  4. Department of Molecular and Cellular Physiology, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH, 45267-0575, USA

    John Lorenz

  5. Cardiovascular Research Center, Mount Sinai School of Medicine, New York, NY, 10029, USA

    Roger J. Hajjar

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  1. Guoli Chen
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  10. Evangelia G. Kranias
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Correspondence to Evangelia G. Kranias.

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G. Chen, X. Zhou contributed to the work equally.

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Chen, G., Zhou, X., Florea, S. et al. Expression of active protein phosphatase 1 inhibitor-1 attenuates chronic beta-agonist-induced cardiac apoptosis. Basic Res Cardiol 105, 573–581 (2010). https://doi.org/10.1007/s00395-010-0106-3

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  • DOI: https://doi.org/10.1007/s00395-010-0106-3

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