Nature Medicine
8, 725 - 730 (2002)
Published online: 10 June 2002; | doi:10.1038/nm719
Mitochondrial death protein Nix is induced in cardiac hypertrophy and triggers apoptotic cardiomyopathyMartin G. Yussman1, Tsuyoshi Toyokawa1, Amy Odley1, Roy A. Lynch4, Guangyu Wu1, 4, Melissa C. Colbert3, Bruce J. Aronow3, John N. Lorenz2
& Gerald W. Dorn II1, 41
Department of Internal Medicine, University of Cincinnati Medical Center, Cincinnati, Ohio, USA
2
Department of Molecular and Cellular Physiology, University of Cincinnati Medical Center, Cincinnati, Ohio, USA
3
Department of Pediatrics, University of Cincinnati Medical Center, Cincinnati, Ohio, USA
4
Department of Cardiovascular Center of the University of Cincinnati Medical Center, Cincinnati, Ohio, USA
Correspondence should be addressed to Gerald W. Dorn II dorngw@ucmail.uc.eduLoss 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 G q-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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