Nix-mediated apoptosis links myocardial fibrosis, cardiac remodeling, and hypertrophy 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.