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

Circulation
Abhinav DiwanGerald W Dorn

Abstract

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. 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 cardiomyopat...Continue Reading

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