Abstract
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+Nix KO 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.
Original language | English (US) |
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Pages (from-to) | 396-404 |
Number of pages | 9 |
Journal | Circulation |
Volume | 117 |
Issue number | 3 |
DOIs | |
State | Published - Jan 2008 |
Externally published | Yes |
Keywords
- Apoptosis
- Cardiomyopathy
- Hypertrophy
ASJC Scopus subject areas
- Cardiology and Cardiovascular Medicine
- Physiology (medical)