p53 Acetylation Exerts Critical Roles in Pressure Overload-Induced Coronary Microvascular Dysfunction and Heart...

Area of Science:

• Cardiovascular Biology
• Molecular Cardiology
• Vascular Physiology

Background:

• Coronary microvascular dysfunction (CMD) contributes to cardiac hypertrophy and heart failure with preserved ejection fraction.
• Currently, no effective treatments exist for CMD.
• Histone acetylation is implicated in the regulation of CMD.

Purpose of the Study:

• To investigate the role of p53 acetylation in CMD.
• To test if acetylation-deficient p53 (p53^4KR) can improve CMD and prevent hypertensive cardiac hypertrophy and heart failure (HF).

Main Methods:

• Utilized a mouse model with acetylation-deficient p53 (p53^4KR).
• Induced cardiac hypertrophy and HF via transverse aortic constriction in wild-type and p53^4KR mice.
• Assessed cardiac function, apoptosis, fibrosis, capillary density, coronary flow reserve, and molecular markers.

Main Results:

• p53^4KR mice exhibited improved cardiac function, reduced apoptosis and fibrosis, and enhanced myocardial capillary density and coronary flow reserve.
• Upregulation of cardiac glycolytic enzymes, glucose transporters, and fructose-2,6-biphosphate was observed in p53^4KR mice.
• In vitro studies showed p53^4KR improved endothelial cell function, proliferation, and angiogenesis, and rescued cardiac dysfunction in SIRT3 knockout mice.

Conclusions:

• p53 acetylation is crucial for coronary microvascular function, cardiac function, and remodeling.
• Acetylation-deficient p53 presents a promising therapeutic strategy for hypertension-induced CMD.
• This approach may prevent the progression from cardiac hypertrophy to heart failure.