The role and regulatory mechanism of HIF-1α in myocardial injury in rats undergoing cardiopulmonary bypass.

BACKGROUND: Hypoxia-inducible factor-1alpha (HIF-1α) is a transcription factor implicated in physiological and pathological responses to hypoxia. The present study aims to investigate the effect and mechanism of HIF-1α on cardiopulmonary bypass (CPB)-related myocardial injury, thereby conferring a theoretical basis for the clinical treatment of myocardial injury in CPB. METHODS: An experimental model of CPB was established in rats by surgery. Adenovirus-packaged overexpression vectors and antiagomiRNA were used to overexpress HIF-1α and NR4A1 or inhibit miR-124-3p expression in rat myocardial tissues, respectively. qRT-PCR and Western blot detected HIF-1α, miR-124-3p, and NR4A1 expression in myocardial tissues. The rat cardiac function was monitored through an echocardiogram. The rat plasma at different stages of CPB was collected, followed by the detection of IL-6, cTnT, CK-MB, and IL-1ß. TUNEL staining measured apoptosis in myocardial tissues. ChIP assay analysed the enrichment of HIF-1α on the miR-124-3p promoter. The binding relationships between HIF-1α and miR-124-3p promoter sequence and between miR-124-3p and NR4A1 3'UTR sequence were confirmed by dual-luciferase reporter assay. RESULTS: HIF-1α expression had no significant change after CPB modelling. Overexpression of HIF-1α improved the cardiac function of CPB rats, decreased plasma IL-6, cTnT, CK-MB, and IL-1ß levels, and reduced TUNEL-positive myocardial cells. HIF-1α was enriched on the miR-124-3p promoter and promoted miR-124-3p expression. miR-124-3p bound to NR4A1 3'UTR sequence and targeted NR4A1 expression. Inhibition of miR-124-3p or overexpression of NR4A1 partially reversed the ameliorative effect of HIF-1α overexpression on myocardial injury in CPB rats. CONCLUSION: Overexpression of HIF-1α can improve myocardial injury in CPB rats via the miR-124-3p/NR4A1 axis.