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Mitochondrial death protein Nix is induced in cardiac hypertrophy and triggers apoptotic cardiomyopathy

Nature Medicine volume 8, pages 725–730 (2002)Cite this article

Abstract

Loss of cardiomyocytes through programmed cell death is a key event in the development of heart failure, but the inciting molecular mechanisms are largely unknown. We used microarray analysis to identify a genetic program for myocardial apoptosis in Gq-mediated and pressure-overload cardiac hypertrophy. A critical component of this apoptotic program was Nix/Bnip3L. Nix localized to mitochondria and caused release of cytochrome c, activation of caspase-3 and apoptotic cell death, when expressed in HEK293 fibroblasts. A previously undescribed truncated Nix isoform, termed sNix, was not targeted to mitochondria but heterodimerized with Nix and protected against Nix-mediated apoptosis. Forced in vivo myocardial expression of Nix resulted in apoptotic cardiomyopathy and rapid death. Conversely, sNix protected against apoptotic peripartum cardiomyopathy in Gαq-overexpressors. Thus, Nix/Bnip3L is upregulated in myocardial hypertrophy, and is both necessary and sufficient for Gq-mediated apoptosis of cardiomyocytes and resulting hypertrophy decompensation.

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Figure 1: Identification and cloning of mouse Nix and sNix.
Figure 2: Confocal analysis of Nix-expressing cells.
Figure 3: Phenotypic analysis of Nix-expressing mice.
Figure 4: Cellular effects of myocardial Nix expression.
Figure 5: Expression of recombinant Nix and sNix in HEK 293 cells.
Figure 6: sNix effects on Gq-peripartum cardiomyopathy.

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Acknowledgements

This work was supported by US National Institutes of Health grants HL58010 and HL59888.

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Authors and Affiliations

  1. Department of Internal Medicine, University of Cincinnati Medical Center, Cincinnati, Ohio, USA

    Martin G. Yussman, Tsuyoshi Toyokawa, Amy Odley, Guangyu Wu & Gerald W. Dorn II

  2. Department of Molecular and Cellular Physiology, University of Cincinnati Medical Center, Cincinnati, Ohio, USA

    John N. Lorenz

  3. Department of Pediatrics, University of Cincinnati Medical Center, Cincinnati, Ohio, USA

    Melissa C. Colbert & Bruce J. Aronow

  4. Department of Cardiovascular Center of the University of Cincinnati Medical Center, Cincinnati, Ohio, USA

    Roy A. Lynch, Guangyu Wu & Gerald W. Dorn II

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  1. Martin G. Yussman
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Correspondence to Gerald W. Dorn II.

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Yussman, M., Toyokawa, T., Odley, A. et al. Mitochondrial death protein Nix is induced in cardiac hypertrophy and triggers apoptotic cardiomyopathy. Nat Med 8, 725–730 (2002). https://doi.org/10.1038/nm719

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