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

Circulation. 2008 Jan 22;117(3):396-404. doi: 10.1161/CIRCULATIONAHA.107.727073. Epub 2008 Jan 4.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Apoptosis*
  • Fibrosis / etiology
  • Fibrosis / pathology*
  • Heart Failure
  • Humans
  • Hypertrophy / etiology
  • Hypertrophy / pathology*
  • Membrane Proteins / physiology
  • Mice
  • Myocardium / pathology*
  • Myocytes, Cardiac / pathology
  • Proto-Oncogene Proteins / physiology*
  • Tumor Suppressor Proteins / physiology
  • Ventricular Remodeling*


  • BNIP3L protein, human
  • Membrane Proteins
  • Proto-Oncogene Proteins
  • Tumor Suppressor Proteins