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

MG Yussman, T Toyokawa, A Odley, RA Lynch, G Wu… - Nature medicine, 2002 - nature.com
MG Yussman, T Toyokawa, A Odley, RA Lynch, G Wu, MC Colbert, BJ Aronow, JN Lorenz…
Nature medicine, 2002nature.com
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 …
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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