Vagus nerve stimulation alleviates hepatic ischemia/reperfusion-induced myocardial injury through AMPK/ULK1/Rab9-mediated alternative mitophagy

Hepatic ischemia/reperfusion (I/R) injury induces distal myocardial injury. Vagus nerve stimulation (VNS) exerts cardioprotective effects by modulating mitophagy under various pathological conditions. In the present study, we investigated the protective effect of VNS against distal myocardial injury induced by hepatic I/R in a rat model, and further investigated whether VNS exerts its cardioprotection by regulating Rab9-dependent alternative mitophagy. A hepatic I/R injury model was established by 1 h of 70% hepatic ischemia followed by 6 h of reperfusion. Sprague–Dawley rats were randomly assigned to four experimental groups: Sham group (sham surgery + sham VNS), I/R group (hepatic I/R + sham VNS); VNS group (hepatic I/R + VNS); and CC group (hepatic I/R + VNS + Compound C; Compound C: 0.2 mg/kg, administered via intraperitoneal injection). VNS was performed throughout the hepatic I/R process. Rats’ heart rate and blood pressure were continuously monitored, with baseline values recorded pre-intervention and dynamic changes tracked during I/R. Liver function, myocardial injury, cardiomyocyte apoptosis, mitochondrial function and morphology. AMPK/ULK1/Rab9 pathway-related protein expression was detected in a rat model of hepatic I/R-induced distal myocardial injury, and we further investigated whether VNS regulates this pathway for cardioprotection. In rats with hepatic I/R injury, VNS treatment preserved hemodynamic stability in the early reperfusion phase, mitigated myocardial injury and apoptosis, and alleviated impaired mitochondrial function as well as structural abnormalities. In addition, VNS activated AMPK and Ulk1 and increased expression of Rab9. The cardioprotective effects of VNS on myocardial and mitochondrial function/structure were partially abrogated by the Compound C. This study indicates that VNS may mitigate remote myocardial injury induced during the early stage of hepatic I/R, through activation of the AMPK/ULK1/Rab9 pathway that acts as an alternative mitophagy mechanism. Targeting Rab9-mediated alternative mitophagy could provide a novel therapeutic strategy for hepatic I/R induced myocardial injury.