title: Mitochondrial death protein Nix is induced in cardiac hypertrophy and triggers apoptotic cardiomyopathy.
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 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.
authors.affiliation: Department of Internal Medicine, University of Cincinnati Medical Center, Cincinnati, Ohio, USA.
authors.forename: Martin G
authors.initials: MG
authors.lastname: Yussman
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Toyokawa
authors.forename: Amy
authors.initials: A
authors.lastname: Odley
authors.forename: Roy A
authors.initials: RA
authors.lastname: Lynch
authors.forename: Guangyu
authors.initials: G
authors.lastname: Wu
authors.forename: Melissa C
authors.initials: MC
authors.lastname: Colbert
authors.forename: Bruce J
authors.initials: BJ
authors.lastname: Aronow
authors.forename: John N
authors.initials: JN
authors.lastname: Lorenz
authors.forename: Gerald W
authors.initials: GW
authors.lastname: Dorn
mesh_terms: 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
chemical_list: C116838:BNIP3L protein, human; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D011994:Recombinant Proteins; D025521:Tumor Suppressor Proteins