biostudies-literatureHe XNHLBI NIH HHSNIGMS NIH HHS826-842https://www.ebi.ac.uk/biostudies/studies/S-EPMC10978286biostudies-literatureUnknown44(4)<h4>Background</h4>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.<h4>Methods</h4>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 (p53^4KR), preventing acetylation at these sites, we test the hypothesis that acetylation-deficient p53^4KR could improve CMD and prevent the progression of hypertensive cardiac hypertrophy and HF. Wild-type and p53^4KR mice were subjected to pressure overload by transverse aortic constriction to induce cardiac hypertrophy and HF.<h4>Results</h4>Echocardiography measurements revealed improved cardiac function together with a reduction of apoptosis and fibrosis in p53^4KR mice. Importantly, myocardial capillary density and coronary flow reserve were significantly improved in p53^4KR mice. Moreover, p53^4KR 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 p53^4KR mice, as well as in p53^4KR mice after transverse aortic constriction. In vitro, p53^4KR significantly improved endothelial cell glycolytic function and mitochondrial respiration and enhanced endothelial cell proliferation and angiogenesis. Similarly, acetylation-deficient p53^4KR significantly improved coronary flow reserve and rescued cardiac dysfunction in SIRT3 (sirtuin 3) knockout mice.<h4>Conclusions</h4>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.Arteriosclerosis, thrombosis, and vascular biologyp53 Acetylation Exerts Critical Roles in Pressure Overload-Induced Coronary Microvascular Dysfunction and Heart Failure in Mice.PMC10978286R01 HL161085P20 GM104357R56 HL164321R01 HL151536He XGu WCantrell ACChen YZeng HChen JXWilliams QAfalsep53 Acetylation Exerts Critical Roles in Pressure Overload-Induced Coronary Microvascular Dysfunction and Heart Failure in Mice.<h4>Background</h4>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.<h4>Methods</h4>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 (p53^4KR), preventing acetylation at these sites, we test the hypothesis that acetylation-deficient p53^4KR could improve CMD and prevent the progression of hypertensive cardiac hypertrophy and HF. Wild-type and p53^4KR mice were subjected to pressure overload by transverse aortic constriction to induce cardiac hypertrophy and HF.<h4>Results</h4>Echocardiography measurements revealed improved cardiac function together with a reduction of apoptosis and fibrosis in p53^4KR mice. Importantly, myocardial capillary density and coronary flow reserve were significantly improved in p53^4KR mice. Moreover, p53^4KR 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 p53^4KR mice, as well as in p53^4KR mice after transverse aortic constriction. In vitro, p53^4KR significantly improved endothelial cell glycolytic function and mitochondrial respiration and enhanced endothelial cell proliferation and angiogenesis. Similarly, acetylation-deficient p53^4KR significantly improved coronary flow reserve and rescued cardiac dysfunction in SIRT3 (sirtuin 3) knockout mice.<h4>Conclusions</h4>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.2024-01-01T00:00:00Z2024 Apr2025-07-13T03:04:44.748Z2025-07-13T03:04:44.748ZS-EPMC109782863832893710.1161/ATVBAHA.123.31960110.1161/atvbaha.123.319601