Effect and Mechanism of Shenqi Lixin Formula on Angiogenesis and Glucose Metabolism in Rats With Heart Failure After Myocardial Infarction

ABSTRACT Post‐myocardial infarction (MI) patients remain at high risk for developing heart failure (HF). This study investigated the therapeutic effects and mechanistic basis of Shenqi Lixin Formula (SQLXF) on angiogenesis and glucose metabolism in MI‐HF. MI‐HF rat models were generated, and myocardial pathology, infarct area, cardiac function, platelet endothelial cell adhesion molecule‐1 (CD31), vascular endothelial growth factor A (VEGFA), hexokinase 2 (HK2), lactate dehydrogenase A (LDHA), lysine demethylase 5B (KDM5B) and ER degradation enhancing alpha‐mannosidase like protein 3 (EDEM3) expressions, glucose consumption, lactate production and extracellular acidification rate (ECAR) were evaluated. Hypoxia‐treated human cardiac microvascular endothelial cells (HCMECs) were used as in vitro models to assess angiogenic capacity. SQLXF intervention and subsequent analyses were performed to determine KDM5B and EDEM3 expression levels, as well as the enrichment of KDM5B and trimethylation of lysine 4 on histone H3 protein subunit (H3K4me3) on the EDEM3 promoter. In animal models, infarct area enlargement, impaired cardiac function, increased glucose consumption, lactate production, and upregulation of CD31, VEGFA, HK2, LDHA and KDM5B expressions were observed, accompanied by reduced EDEM3 expression. SQLXF administration improved cardiac function, promoted angiogenesis, normalised glucose metabolism, inhibited KDM5B and restored EDEM3 expression. In HCMECs, hypoxia suppressed EDEM3, angiogenesis and metabolic stability while increasing KDM5B expression; these alterations were reversed by high‐dose SQLXF. Mechanistically, KDM5B inhibited EDEM3 transcription by reducing H3K4me3 enrichment, whereas SQLXF enhanced H3K4me3 and relieved KDM5B‐mediated repression. KDM5B overexpression or EDEM3 knockdown attenuated the beneficial effects of SQLXF.