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Published on: April 13, 2015
p53 Acetylation Exerts Critical Roles in Pressure Overload-Induced Coronary Microvascular Dysfunction and Heart
Xiaochen He1, Aubrey C Cantrell2, Quinesha A Williams2
1Department of Physiology and Biophysics (X.H., Y.C.), University of Mississippi Medical Center, School of Medicine, Jackson.
Insights
Acetylation-deficient p53 improved coronary microvascular function and cardiac function in a mouse model of hypertension. This suggests a potential therapeutic strategy for preventing heart failure progression.
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 (p534KR) can improve CMD and prevent hypertensive cardiac hypertrophy and heart failure (HF).
Main Methods:
- Utilized a mouse model with acetylation-deficient p53 (p534KR).
- Induced cardiac hypertrophy and HF via transverse aortic constriction in wild-type and p534KR mice.
- Assessed cardiac function, apoptosis, fibrosis, capillary density, coronary flow reserve, and molecular markers.
Main Results:
- p534KR 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 p534KR mice.
- In vitro studies showed p534KR 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.
Background:
Coronary microvascular dysfunction (CMD) has been shown to contribute to cardiac hypertrophy and heart failure (HF) with preserved ejection fraction. At this point, there are no proven treatments for CMD.
Methods:
We have shown that histone acetylation may play a critical role in the regulation of CMD. By using a mouse model that replaces lysine with arginine at residues K98, K117, K161, and K162R of p53 (p534KR), preventing acetylation at these sites, we test the hypothesis that acetylation-deficient p534KR could improve CMD and prevent the progression of hypertensive cardiac hypertrophy and HF. Wild-type and p534KR mice were subjected to pressure overload by transverse aortic constriction to induce cardiac hypertrophy and HF.
Results:
Echocardiography measurements revealed improved cardiac function together with a reduction of apoptosis and fibrosis in p534KR mice. Importantly, myocardial capillary density and coronary flow reserve were significantly improved in p534KR mice. Moreover, p534KR upregulated the expression of cardiac glycolytic enzymes and Gluts (glucose transporters), as well as the level of fructose-2,6-biphosphate; increased PFK-1 (phosphofructokinase 1) activity; and attenuated cardiac hypertrophy. These changes were accompanied by increased expression of HIF-1α (hypoxia-inducible factor-1α) and proangiogenic growth factors. Additionally, the levels of SERCA-2 were significantly upregulated in sham p534KR mice, as well as in p534KR mice after transverse aortic constriction. In vitro, p534KR significantly improved endothelial cell glycolytic function and mitochondrial respiration and enhanced endothelial cell proliferation and angiogenesis. Similarly, acetylation-deficient p534KR significantly improved coronary flow reserve and rescued cardiac dysfunction in SIRT3 (sirtuin 3) knockout mice.
Conclusions:
Our data reveal the importance of p53 acetylation in coronary microvascular function, cardiac function, and remodeling and may provide a promising approach to improve hypertension-induced CMD and to prevent the transition of cardiac hypertrophy to HF.
