β-Hydroxybutyrate Facilitates Homeostasis of Hypoxic Endothelial Cells After Myocardial Infarction via Histone Lysine β-Hydroxybutyrylation of CPT1A

Myocardial infarction (MI) initiates a robust angiogenic response crucial for tissue repair. β-hydroxybutyrate (BHB) is an essential circulating metabolite, and its role in angiogenesis under pathological conditions remains unclear. We evaluated the coronary collateral circulation in 114 patients with MI and investigated its correlation with serum BHB levels. High BHB levels were found to correlate with better collateral circulation. Moreover, BHB promotes angiogenesis post-MI in vivo and in vitro. Mechanistically, BHB modulates the epigenetic landscape in hypoxic endothelial cells by increasing H3K9bhb levels associated with the transcriptional activation of angiogenesis-related genes and enhancing chromatin accessibility at loci associated with these genes. The integrated analysis of RNA sequencing, cleavage under targets and tagmentation, and assay for transposase-accessible chromatin with sequencing identified carnitine palmitoyltransferase 1a as a key proangiogenic target. Thus, BHB nutritional supplementation may represent a promising therapeutic strategy for ischemic heart disease, with high potential for clinical translation.