BACKGROUND: Pathological cardiac hypertrophy inevitably remodels, leading to functional decompensation. Although modulation of apoptosis-regulating genes occurs in cardiac hypertrophy, a causal role for programmed cardiomyocyte death in left ventricular (LV) remodeling has not been established. METHODS AND RESULTS: We targeted the gene for proapoptotic Nix, which is transcriptionally upregulated in pressure overload and Gq-dependent hypertrophies, in the mouse germ line or specifically in cardiomyocytes (knockout [KO]) and conditionally overexpressed it in the heart (transgenic [TG]). Conditional forced Nix expression acted synergistically with the prohypertrophic Gq transgene to increase cardiomyocyte apoptosis (0.8+/-0.1% in GqTG versus 7.8+/-0.6% in GqTG+NixTG; P<0.001), causing lethal cardiomyopathy with LV dilation and depressed systolic function (percent fractional shortening, 39+/-4 versus 23+/-4; P=0.042). In the reciprocal experiment, germ-line Nix ablation significantly reduced cardiomyocyte apoptosis (4.8+/-0.2% in GqTG+NixKO versus 8.4+/-0.5% in GqTG; P=0.001), which improved percent fractional shortening (43+/-3% versus 27+/-3%; P=0.017), attenuated LV remodeling, and largely prevented lethality in the Gq peripartum model of apoptotic cardiomyopathy. Cardiac-specific (Nkx2.5-Cre) Nix KO mice subjected to transverse aortic constriction developed significantly less LV dilation by echocardiography and magnetic resonance imaging, maintained concentric remodeling, and exhibited preserved LV ejection fraction (61+/-2% in transverse aortic constriction cardiac Nix KO versus 36+/-6% in transverse aortic constriction wild-type mice; P=0.003) at 9 weeks, with reduced cardiomyocyte apoptosis at day 4 (1.70+/-0.21% versus 2.73+/-0.35%; P=0.032). CONCLUSIONS: Nix-induced cardiomyocyte apoptosis is a major determinant of adverse remodeling in pathological hypertrophies, a finding that suggests therapeutic value for apoptosis inhibition to prevent cardiomyopathic decompensation.
BACKGROUND: Pathological cardiac hypertrophy inevitably remodels, leading to functional decompensation. Although modulation of apoptosis-regulating genes occurs in cardiac hypertrophy, a causal role for programmed cardiomyocyte death in left ventricular (LV) remodeling has not been established. METHODS AND RESULTS: We targeted the gene for proapoptotic Nix, which is transcriptionally upregulated in pressure overload and Gq-dependent hypertrophies, in the mouse germ line or specifically in cardiomyocytes (knockout [KO]) and conditionally overexpressed it in the heart (transgenic [TG]). Conditional forced Nix expression acted synergistically with the prohypertrophic Gq transgene to increase cardiomyocyte apoptosis (0.8+/-0.1% in GqTG versus 7.8+/-0.6% in GqTG+NixTG; P<0.001), causing lethal cardiomyopathy with LV dilation and depressed systolic function (percent fractional shortening, 39+/-4 versus 23+/-4; P=0.042). In the reciprocal experiment, germ-line Nix ablation significantly reduced cardiomyocyte apoptosis (4.8+/-0.2% in GqTG+NixKO versus 8.4+/-0.5% in GqTG; P=0.001), which improved percent fractional shortening (43+/-3% versus 27+/-3%; P=0.017), attenuated LV remodeling, and largely prevented lethality in the Gq peripartum model of apoptotic cardiomyopathy. Cardiac-specific (Nkx2.5-Cre) Nix KO mice subjected to transverse aortic constriction developed significantly less LV dilation by echocardiography and magnetic resonance imaging, maintained concentric remodeling, and exhibited preserved LV ejection fraction (61+/-2% in transverse aortic constriction cardiac Nix KO versus 36+/-6% in transverse aortic constriction wild-type mice; P=0.003) at 9 weeks, with reduced cardiomyocyte apoptosis at day 4 (1.70+/-0.21% versus 2.73+/-0.35%; P=0.032). CONCLUSIONS:Nix-induced cardiomyocyte apoptosis is a major determinant of adverse remodeling in pathological hypertrophies, a finding that suggests therapeutic value for apoptosis inhibition to prevent cardiomyopathic decompensation.
Authors: Anita S Gálvez; Eric W Brunskill; Yehia Marreez; Bonnie J Benner; Kelly M Regula; Lorrie A Kirschenbaum; Gerald W Dorn Journal: J Biol Chem Date: 2005-11-16 Impact factor: 5.157
Authors: Stefan Donath; Peifeng Li; Christian Willenbockel; Nidal Al-Saadi; Volkmar Gross; Thomas Willnow; Michael Bader; Ulrich Martin; Johann Bauersachs; Kai C Wollert; Rainer Dietz; Rüdiger von Harsdorf Journal: Circulation Date: 2006-02-27 Impact factor: 29.690
Authors: Vanessa P M van Empel; Anne T Bertrand; Roel van der Nagel; Sawa Kostin; Pieter A Doevendans; Harry J Crijns; Elly de Wit; Wim Sluiter; Susan L Ackerman; Leon J De Windt Journal: Circ Res Date: 2005-06-02 Impact factor: 17.367
Authors: Faisal Syed; Amy Odley; Harvey S Hahn; Eric W Brunskill; Roy A Lynch; Yehia Marreez; Atsushi Sanbe; Jeffrey Robbins; Gerald W Dorn Journal: Circ Res Date: 2004-11-11 Impact factor: 17.367
Authors: Scot J Matkovich; Abhinav Diwan; Justin L Klanke; Daniel J Hammer; Yehia Marreez; Amy M Odley; Eric W Brunskill; Walter J Koch; Robert J Schwartz; Gerald W Dorn Journal: Circ Res Date: 2006-09-28 Impact factor: 17.367
Authors: Giovanni Esposito; Antonio Rapacciuolo; Sathyamangla V Naga Prasad; Hideyuki Takaoka; Steven A Thomas; Walter J Koch; Howard A Rockman Journal: Circulation Date: 2002-01-01 Impact factor: 29.690