{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["He X"],"funding":["NHLBI NIH HHS","NIGMS NIH HHS"],"pagination":["826-842"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC10978286"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["44(4)"],"pubmed_abstract":["<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<sup>4KR</sup>), preventing acetylation at these sites, we test the hypothesis that acetylation-deficient p53<sup>4KR</sup> could improve CMD and prevent the progression of hypertensive cardiac hypertrophy and HF. Wild-type and p53<sup>4KR</sup> 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<sup>4KR</sup> mice. Importantly, myocardial capillary density and coronary flow reserve were significantly improved in p53<sup>4KR</sup> mice. Moreover, p53<sup>4KR</sup> 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<sup>4KR</sup> mice, as well as in p53<sup>4KR</sup> mice after transverse aortic constriction. In vitro, p53<sup>4KR</sup> significantly improved endothelial cell glycolytic function and mitochondrial respiration and enhanced endothelial cell proliferation and angiogenesis. Similarly, acetylation-deficient p53<sup>4KR</sup> 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."],"journal":["Arteriosclerosis, thrombosis, and vascular biology"],"pubmed_title":["p53 Acetylation Exerts Critical Roles in Pressure Overload-Induced Coronary Microvascular Dysfunction and Heart Failure in Mice."],"pmcid":["PMC10978286"],"funding_grant_id":["R01 HL161085","P20 GM104357","R56 HL164321","R01 HL151536"],"pubmed_authors":["He X","Gu W","Cantrell AC","Chen Y","Zeng H","Chen JX","Williams QA"],"additional_accession":[]},"is_claimable":false,"name":"p53 Acetylation Exerts Critical Roles in Pressure Overload-Induced Coronary Microvascular Dysfunction and Heart Failure in Mice.","description":"<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<sup>4KR</sup>), preventing acetylation at these sites, we test the hypothesis that acetylation-deficient p53<sup>4KR</sup> could improve CMD and prevent the progression of hypertensive cardiac hypertrophy and HF. Wild-type and p53<sup>4KR</sup> 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<sup>4KR</sup> mice. Importantly, myocardial capillary density and coronary flow reserve were significantly improved in p53<sup>4KR</sup> mice. Moreover, p53<sup>4KR</sup> 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<sup>4KR</sup> mice, as well as in p53<sup>4KR</sup> mice after transverse aortic constriction. In vitro, p53<sup>4KR</sup> significantly improved endothelial cell glycolytic function and mitochondrial respiration and enhanced endothelial cell proliferation and angiogenesis. Similarly, acetylation-deficient p53<sup>4KR</sup> 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.","dates":{"release":"2024-01-01T00:00:00Z","publication":"2024 Apr","modification":"2025-07-13T03:04:44.748Z","creation":"2025-07-13T03:04:44.748Z"},"accession":"S-EPMC10978286","cross_references":{"pubmed":["38328937"],"doi":["10.1161/ATVBAHA.123.319601","10.1161/atvbaha.123.319601"]}}