{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,31]],"date-time":"2026-10-31T20:46:49Z","timestamp":1793479609964,"version":"4.5.0"},"reference-count":56,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"7","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2025,3,28]]},"abstract":"<jats:sec>\n            <jats:title>BACKGROUND:<\/jats:title>\n            <jats:p>Acute myocardial infarction (MI) remains one of the major causes of death worldwide, and innovative treatment strategies for MI represent a major challenge in cardiovascular medicine. Caloric restriction (CR) is the most potent nonpharmacological intervention known to prevent age-related disorders and extend lifespan. CR reduces glycolysis and elevates ketone body metabolism. However, whether and how CR or ketone body prevents the progression of MI remains poorly defined.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>METHODS:<\/jats:title>\n            <jats:p>Mice treated with CR and \u03b2-hydroxybutyrate (\u03b2-OHB) underwent MI induced by ligation of the left anterior descending coronary artery. Cardiac function was assessed by echocardiographic measurements. Histological analysis, fluorescence-activated cell sorting, and immunofluorescence were used to assess myocardial neovascularization and macrophage filtration. The interaction and modification of \u03b2-OHB on PHD2 were analyzed by molecular docking, cellular thermal shift assay, liquid chromatography with tandem mass spectrometry, and coimmunoprecipitation. Macrophage-specific PHD2 K239R and K385R knock-in mice were used to determine the functional significance of \u03b2-OHB\/PHD2 axis in vivo.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>RESULTS:<\/jats:title>\n            <jats:p>Twelve weeks of CR markedly rescued postinfarction cardiac function by enhancing neovascularization. CR significantly increased circulating and cardiac ketone bodies, including \u03b2-OHB and acetoacetate. We identified \u03b2-OHB but not acetoacetate selectively targeted macrophages to stimulate VEGF (vascular endothelial growth factor) production in the peri-infarct area to promote neovascularization and cardiac repair. Mechanistically, \u03b2-OHB binds to and induces lysine \u03b2-hydroxybutyrylation of PHD2 at lysines 239 and 385, thus blocking its function in the hydroxylation of HIF-1\u03b1 (hypoxia-inducible factor 1\u03b1) and resulting in enhanced HIF1\u03b1-dependent VEGF transcription and secretion. More importantly, specific PHD2 lys239 and lys385 mutations in macrophages abolished the preventive effects of exogenous \u03b2-OHB on MI in mice.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>CONCLUSIONS:<\/jats:title>\n            <jats:p>These data reveal a novel regulation of lysine \u03b2-hydroxybutyrylation on PHD2 and demonstrate a promising and therapeutic role for \u03b2-OHB\/PHD2 in effectively accelerating neovascularization and preserving heart function after cardiac ischemia.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circresaha.124.325179","type":"journal-article","created":{"date-parts":[[2025,2,17]],"date-time":"2025-02-17T10:00:24Z","timestamp":1739786424000},"page":"704-718","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":21,"title":["\u03b2-Hydroxybutyrate Facilitates Postinfarction Cardiac Repair via Targeting 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and Technology, Wuhan, China."},{"name":"Hubei Key Laboratory of Metabolic Abnormalities and Vascular Aging (C.W., W.X., S.J., Y.W., J.S., X.G., K.H.), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yichen","family":"Wu","sequence":"additional","affiliation":[{"name":"Clinic Center of Human Gene Research, Union Hospital (C.W., W.X., S.J., Y.W., J.S., X.G., K.H.), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China."},{"name":"Department of Cardiology, Union Hospital (W.X., S.J., Y.W., X.G., K.H.), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China."},{"name":"Hubei Key Laboratory of Metabolic Abnormalities and Vascular Aging (C.W., W.X., S.J., Y.W., J.S., X.G., K.H.), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 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