The mechanism of dexmedetomidine regulation of the HIF-1α/FUNDC1 axis in myocardial ischemia/reperfusion injury

Objective: Myocardial ischemia/reperfusion injury (MIRI) is a life -threatening event that typically follows reperfusion therapy for myocardial infarction. Regarding the effects of dexmedetomidine (Dex) in MIRI, we explored its specific mechanism.

Methods: The MIRI rat model was treated with Dex, Topotecan [a hypoxia-inducible factor-1α (HIF1α) inhibitor], and lentiviral overexpressing FUN14 domain-containing protein 1 (Lv-oe-FUNDC1), with rat heart rate analysis. The pathological damage of rat myocardial tissue was evaluated by hematoxylin-eosin (HE) and Masson staining. Positive expression levels of PTEN-induced kinase 1 (PINK1), Parkin, microtubule-associated protein 1 light chain 3 (LC3) II/I, p62 and Beclin1 proteins, HIF-1α and FUNDC1 messenger RNA (mRNA), and HIF-1α and FUNDC1 were assessed by western blot, reverse transcription-quantitative polymerase chain reaction (RT-qPCR), and immunohistochemical staining, respectively. HIF-1α-FUNDC1 binding sites and targeted binding relationships were predicted and verified via databases and dual-luciferase assay. HIF-1α enrichment levels in the FUNDC1 promoter region were evaluated using a ChIP assay.

Results: MIRI rats exhibited myocardial injury and severe myocardial dysfunction, with elevated left ventricular diastolic pressure and p62 expression, reduced left ventricular systolic pressure, and maximum rate of change in left ventricular pressure and PINK1, Parkin, LC3 II/I ratio and Beclin-1 protein levels, which were reversed by Dex treatment. MIRI rats had increased HIF-1α and FUNDC1 expression levels, which were further boosted after Dex treatment. Dex promoted mitophagy to ameliorate myocardial injury in MIRI rats via the HIF-1α/FUNDC1 axis.

Conclusion: Dex promoted mitophagy by up-regulating HIF-1α to facilitate the transcriptional expression of FUNDC1, thereby ameliorating myocardial injury in MIRI rats."