Combined administration of dexmedetomidine and propofol mitigates myocardial ischemia/reperfusion injury by modulating the Akt/mTOR/Nrf2 axis to suppress ferroptosis.

Myocardial ischemia/reperfusion injury (MIRI) poses a significant threat to human health, necessitating the development of novel therapeutic strategies. Although the protective effects of dexmedetomidine (Dex) and propofol (PPF) in mitigating MIRI have been documented, the mechanisms underlying their synergistic effects remain unclear. In an in vivo model, rats underwent surgical induction of MIRI, followed by intravenous administration of Dex and/or PPF 10 or 20 min before reperfusion. Myocardial function, markers of myocardial injury, and protein expression levels of the protein kinase B (Akt)/mammalian target of rapamycin (mTOR) and nuclear factor erythroid 2-related factor 2 (Nrf2)/glutathione peroxidase 4 (Gpx4) pathways were assessed. In in vitro model, H9C2 cardiomyocytes were subjected to hypoxia/reoxygenation (H/R), and the following parameters were evaluated: protein expression levels of phosphorylated mTOR and the mRNA level of Nrf2 and Nrf2, cell viability, lactate dehydrogenase concentration, and reactive oxygen species levels. Co-immunoprecipitation assays were conducted to investigate the interplay between the Akt/mTOR and Nrf2/Gpx4 signaling pathways (a schematic representation is provided in Figure 1). The combined administration of Dex and PPF demonstrated superior efficacy compared to either agent alone in mitigating MIRI and H/R-induced injuries. This was evidenced by improved myocardial function, reduced myocardial injury, and inhibition of ferroptosis through modulation of the Akt/mTOR and Nrf2/Gpx4 pathways and their interaction. In conclusion, the combination of Dex and PPF alleviates MIRI by modulating the interaction between the Akt/mTOR and Nrf2/Gpx4 pathways to inhibit ferroptosis, providing a promising therapeutic strategy for MIRI.