{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T10:54:54Z","timestamp":1778151294401,"version":"3.51.4"},"reference-count":78,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"4","license":[{"start":{"date-parts":[[2024,4,1]],"date-time":"2024-04-01T00:00:00Z","timestamp":1711929600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["ATVB"],"published-print":{"date-parts":[[2024,4]]},"abstract":"<jats:sec>\n            <jats:title>BACKGROUND:<\/jats:title>\n            <jats:p>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.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>METHODS:<\/jats:title>\n            <jats:p>\n              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\n              <jats:sup>4KR<\/jats:sup>\n              ), preventing acetylation at these sites, we test the hypothesis that acetylation-deficient p53\n              <jats:sup>4KR<\/jats:sup>\n              could improve CMD and prevent the progression of hypertensive cardiac hypertrophy and HF. Wild-type and p53\n              <jats:sup>4KR<\/jats:sup>\n              mice were subjected to pressure overload by transverse aortic constriction to induce cardiac hypertrophy and HF.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>RESULTS:<\/jats:title>\n            <jats:p>\n              Echocardiography measurements revealed improved cardiac function together with a reduction of apoptosis and fibrosis in p53\n              <jats:sup>4KR<\/jats:sup>\n              mice. Importantly, myocardial capillary density and coronary flow reserve were significantly improved in p53\n              <jats:sup>4KR<\/jats:sup>\n              mice. Moreover, p53\n              <jats:sup>4KR<\/jats:sup>\n              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-1\u03b1 (hypoxia-inducible factor-1\u03b1) and proangiogenic growth factors. Additionally, the levels of SERCA-2 were significantly upregulated in sham p53\n              <jats:sup>4KR<\/jats:sup>\n              mice, as well as in p53\n              <jats:sup>4KR<\/jats:sup>\n              mice after transverse aortic constriction. In vitro, p53\n              <jats:sup>4KR<\/jats:sup>\n              significantly improved endothelial cell glycolytic function and mitochondrial respiration and enhanced endothelial cell proliferation and angiogenesis. Similarly, acetylation-deficient p53\n              <jats:sup>4KR<\/jats:sup>\n              significantly improved coronary flow reserve and rescued cardiac dysfunction in SIRT3 (sirtuin 3) knockout mice.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>CONCLUSIONS:<\/jats:title>\n            <jats:p>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.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/atvbaha.123.319601","type":"journal-article","created":{"date-parts":[[2024,2,8]],"date-time":"2024-02-08T10:00:35Z","timestamp":1707386435000},"page":"826-842","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":20,"title":["p53 Acetylation Exerts Critical Roles in Pressure Overload\u2013Induced Coronary Microvascular Dysfunction and Heart Failure in Mice"],"prefix":"10.1161","volume":"44","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8266-5895","authenticated-orcid":true,"given":"Xiaochen","family":"He","sequence":"first","affiliation":[{"name":"Department of Physiology and Biophysics (X.H., Y.C.), University of Mississippi Medical Center, School of Medicine, Jackson."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0686-3443","authenticated-orcid":true,"given":"Aubrey C.","family":"Cantrell","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology (A.C.C., Q.A.W., J.-X.C., H.Z.), University of Mississippi Medical Center, School of Medicine, Jackson."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Quinesha A.","family":"Williams","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology (A.C.C., Q.A.W., J.-X.C., H.Z.), University of Mississippi Medical Center, School of Medicine, Jackson."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wei","family":"Gu","sequence":"additional","affiliation":[{"name":"Department of Pathology and Cell Biology, Columbia University, Institute for Cancer Genetics, New York, NY (W.G.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4059-7847","authenticated-orcid":true,"given":"Yingjie","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics (X.H., Y.C.), University of Mississippi Medical Center, School of Medicine, Jackson."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9203-4336","authenticated-orcid":true,"given":"Jian-Xiong","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology (A.C.C., Q.A.W., J.-X.C., H.Z.), University of Mississippi Medical Center, 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