BCAA exaggerated acute and chronic ischemic heart disease through promotion of NLRP3 via Sirt1.

The study investigated the role and mechanism of branched chain amino acid (BCAA) metabolism in acute myocardial injury and ventricular remodeling post-myocardial infarction. This research employed an integrated approach, combining molecular biology with metabolomics, to investigate the influence of BCAA on acute and chronic myocardial injury both in vivo and in vitro, respectively. In acute myocardial injury, BCAA significantly aggravated acute myocardial injury as demonstrated by remarkably worsen cardiac function and exacerbated biochemical abnormalities, and increased infarct size. Furthermore, BCAA supplementation aggravated the defective metabolism of BCAA by inhibiting the activities of BCAT2, BCKDH and PP2Cm. Interestingly, BCAA dose-dependently promoted pyroptosis in cardiomyocytes via NLRP3/ASC/Caspase-1 activation and cleaved GSDMD in acute myocardial injury. On the other hand, in long-term myocardial infarction (L-MI) induced remodeling, BCAA aggravated the ventricular remodeling in L-MI, and exacerbated the impairment in BCAA metabolism by inhibiting the activities of BCAT2, BCKDH, and PP2Cm. Interestingly, BCAA promoted inflammation in cardiac fibroblasts (CF) in dose-dependently. This process was mediated by inhibiting Sirt1 and enhancing NLRP3 acetylation, thereby activating the NLRP3 inflammasome and promoting CF migration, but without the trigger of pyroptosis. While Knockdown of Sirt1 markedly inhibited NLRP3 activation induced by BCAA in CF. In summary, this study provided a theoretical foundation for developing novel strategies to prevent and treat cardiovascular diseases, and offered valuable guidance for the dietary management of patients with myocardial injury.