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Novel mechanisms for caspase inhibition protecting cardiac function with chronic pressure overload

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Abstract

Myocyte apoptosis is considered a major mechanism in the pathogenesis of heart failure. Accordingly, manipulations that inhibit apoptosis are assumed to preserve cardiac function by maintaining myocyte numbers. We tested this assumption by examining the effects of caspase inhibition (CI) on cardiac structure and function in C57BL/6 mouse with pressure overload model induced by transverse aortic constriction (TAC). CI preserved left ventricular (LV) function following TAC compared with the vehicle. TAC increased apoptosis in non-myocytes more than in myocytes and these increases were blunted more in non-myocytes by CI. Total myocyte number, however, did not differ significantly among control and TAC groups and there was no correlation between myocyte number and apoptosis, but there was a strong correlation between myocyte number and an index of myocyte proliferation, Ki67-positive myocytes. Despite comparable pressure gradients, LV hypertrophy was less in the CI group, likely attributable to decreased wall stress. Since changes in myocyte numbers did not account for protection from TAC, several other CI-mediated mechanisms were identified including: (a) lessening of TAC-induced fibrosis, (b) augmentation of isolated myocyte contractility, and (c) increased angiogenesis and Ki67-positive myocytes, which were due almost entirely to the non-myocyte apoptosis, but not myocyte apoptosis, with CI. CI maintained LV function following TAC not by protecting against myocyte loss, but rather by augmenting myocyte contractile function, myocyte proliferation, and angiogenesis resulting in reduced LV wall stress, hypertrophy, and fibrosis.

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Acknowledgments

This work was supported by the National Institutes of Health [Grant number: HL093481, HL106511, HL033107, HL095888, HL69020, HL60665, and AG27211].

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, 185 South Orange Ave, MSB G-626, Newark, NJ, 07103, USA

    Misun Park, Stephen F. Vatner, Lin Yan, Shumin Gao, Seunghun Yoon, Grace Jung Ah Lee & Lai-Hua Xie

  2. Department of Medicine, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, NJ, USA

    Dorothy E. Vatner

  3. Department of Medicine and Cell Biology, Wilf Family, Cardiovascular Research Institute, Albert Einstein College of Medicine, Bronx, NY, USA

    Richard N. Kitsis

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  1. Misun Park
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Correspondence to Misun Park.

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Park, M., Vatner, S.F., Yan, L. et al. Novel mechanisms for caspase inhibition protecting cardiac function with chronic pressure overload. Basic Res Cardiol 108, 324 (2013). https://doi.org/10.1007/s00395-012-0324-y

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  • DOI: https://doi.org/10.1007/s00395-012-0324-y

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