Mitochondrial death protein Nix is induced in cardiac hypertrophy and triggers apoptotic cardiomyopathy.
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 G(alpha)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.
Yussman
Martin G
MG
Department of Internal Medicine, University of Cincinnati Medical Center, Cincinnati, Ohio, USA.
Toyokawa
Tsuyoshi
T
Odley
Amy
A
Lynch
Roy A
RA
Wu
Guangyu
G
Colbert
Melissa C
MC
Aronow
Bruce J
BJ
Lorenz
John N
JN
Dorn
Gerald W
GW
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002312:Cardiomyopathy, Hypertrophic / Q000473:pathology*; D003001:Cloning, Molecular; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000473:pathology / Q000502:physiology*; D008969:Molecular Sequence Data; D011518:Proto-Oncogene Proteins; D011994:Recombinant Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D025521:Tumor Suppressor Proteins
C116838:BNIP3L protein, human; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D011994:Recombinant Proteins; D025521:Tumor Suppressor Proteins