Vagus nerve stimulation alleviates myocardial injury following hepatic ischemia-reperfusion in rats by inhibiting ferroptosis via the activation of the SLC7A11/GPX4 axis

Vagus nerve stimulation (VNS) exhibits protective effects against remote organ injury following ischemia-reperfusion (I/R). However, its effects on acute myocardial injury induced by hepatic I/R in rats, and the underlying mechanisms, remain unclear.

VNS protects against myocardial injury from hepatic ischemia-reperfusion, likely by inhibiting oxidative stress and ferroptosis through activation of the SLC7A11/GPX4 axis.

Thirty male rats were randomly assigned to five groups: Sham, I/R, VNS, VNS + Erastin, and VNS + DMSO. A hepatic I/R injury model was established by occluding the arterial and portal veins of the left and middle lobes of the liver for 1 h followed by 6 h of reperfusion. VNS was performed throughout the hepatic I/R process. Erastin was administered intraperitoneally 60 min before hepatic ischemia. Blood samples were collected from the left common carotid artery post-reperfusion to measure liver injury markers (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]) and the myocardial injury marker (cardiac troponin I [cTnI]). Left ventricular myocardial tissue was also collected for ultrastructural analysis via transmission electron microscopy, reactive oxygen species (ROS) detection using dihydroethidium staining, and measurements of Fe2⁺ levels, malondialdehyde (MDA) concentration, glutathione (GSH) levels, and superoxide dismutase (SOD) activity. Western blotting assessed the expression of ferroptosis-related proteins SLC7A11 and GPX4 in the myocardial tissue.

VNS significantly reduced serum levels of ALT, AST, and cTnI, while also mitigating mitochondrial damage in cardiomyocytes. Additionally, VNS decreased ROS levels, alleviated iron overload, and reduced lipid peroxidation in myocardial tissue. These protective effects were associated with the activation of the SLC7A11/GPX4 axis, as evidenced by increased expression of these proteins in the VNS group. However, the cardioprotective effects of VNS were negated by the ferroptosis activator erastin, indicating that ferroptosis is involved in VNS-mediated cardioprotection.