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

Area of Science:

• Cardiovascular Biology
• Molecular Cardiology
• Cell Death Mechanisms

Background:

• Pathological cardiac hypertrophy leads to detrimental left ventricular (LV) remodeling and functional decline.
• While apoptosis-regulating genes are modulated in hypertrophy, the direct role of programmed cardiomyocyte death in LV remodeling remains unclear.

Purpose of the Study:

• To investigate the causal role of the proapoptotic gene Nix in cardiac hypertrophy and left ventricular remodeling.
• To determine if targeting Nix-induced cardiomyocyte apoptosis can prevent adverse cardiac remodeling.

Main Methods:

• Generated Nix knockout (KO) and transgenic (TG) mouse models, with cardiac-specific and germline modifications.
• Utilized pressure overload models (Gq transgene, transverse aortic constriction) to induce cardiac hypertrophy.
• Assessed cardiomyocyte apoptosis, LV remodeling, systolic function, and survival rates using echocardiography, MRI, and histological analyses.

Main Results:

• Forced Nix expression exacerbated cardiomyocyte apoptosis and led to lethal cardiomyopathy with LV dilation and systolic dysfunction.
• Nix ablation significantly reduced cardiomyocyte apoptosis, improved cardiac function, attenuated LV remodeling, and prevented lethality in hypertrophic models.
• Cardiac-specific Nix KO mice subjected to transverse aortic constriction showed preserved LV ejection fraction and reduced remodeling compared to wild-type controls.

Conclusions:

• Nix-induced cardiomyocyte apoptosis is a key driver of adverse remodeling in pathological cardiac hypertrophy.
• Inhibiting Nix-mediated apoptosis holds therapeutic potential for preventing heart failure progression and cardiomyopathic decompensation.