AIM This study investigated alterations in the plasma bile acid pool during myocardial ischemia/reperfusion injury (MI/RI) in diabetes and explored the role and mechanism of deoxycholic acid (DCA) in diabetic MI/RI.
METHODS Plasma bile acids from C57BL/6J mice were profiled using targeted metabolomics via ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS).In vivocardiac function was assessed by echocardiography, myocardial fibrosis by Masson's trichrome staining, and cardiac angiogenesis by CD31 immunohistochemistry.In vitrotube formation assays evaluated the angiogenic capacity of vascular endothelial cells. RNA sequencing (RNA-Seq), quantitative real-time PCR (qRT-PCR), and Western blotting were employed to elucidate downstream mechanisms.
RESULTS Targeted bile acid metabolomics revealed a significant decrease in plasma DCA levels (P<0.01) in diabetic MI/RI mice compared to non-diabetic MI/RI mice. Exogenous DCA supplementation markedly improved cardiac function, reduced myocardial fibrosis (P<0.01), and enhanced angiogenesis (P<0.01) in diabetic MI/RI mice. In vitro, DCA significantly promoted endothelial cell tube formation (P<0.01). Mechanistic studies demonstrated that DCA exerts its cardioprotective effects by activating the TGR5 receptor, leading to the upregulation of a cascade of pro-angiogenic molecules and enhanced angiogenesis.
CONCLUSION Impaired deoxycholic acid (DCA) signaling worsens cardiac susceptibility in diabetes with MI/RI. Therapeutic activation of the DCA-TGR5 pathway enhances microvascular neovascularization and mitigates myocardial damage, revealing a metabolic intervention strategy.
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