Activation of GPR81 protects against myocardial ischemia-reperfusion injury under aberrant glucose metabolism condition by modulating VILIP-1/GRK2/GLUT4 pathway.

Myocardial ischemia/reperfusion (I/R) injury is a major contributor to cardiovascular diseases. Bulk RNA sequencing data revealed 1214 differentially expressed genes (DEGs) between I/R and sham groups. Combination of in vivo and in vitro experiments, with the pharmacological activation of G protein-coupled receptor 81 (GPR81) with 3-Chloro-5-hydroxybenzoic acid (3'5-CHBA), GPR81 antagonist 3-hydroxy-butyrate (3-OBA) and GRK2 inhibitor paroxetine to research molecular mechanisms underlying cardioprotection. Activation of GPR81 with 3'5-CHBA reduced infarct size, improved left ventricular ejection fraction and fractional shortening, and restored conduction velocity and activation time in the I/R group. Furthermore, GPR81 activation enhanced glucose uptake in HL-1 cardiomyocytes subjected to oxygen-glucose deprivation/reoxygenation (OGD/R), a cellular model of I/R injury, and increased the expression of glucose transporter type 4 (GLUT4) at the cardiomyocyte membrane. Mechanistically, GPR81 activation increased the expression of visinin-like protein 1 (VILIP-1) and GLUT4, while it reduced G protein-coupled receptor kinase 2 (GRK2) expression, resulting in enhanced glucose uptake and reduced cell death. These protective effects were reversed upon inhibition of GPR81 using 3-hydroxy-butyrate (3-OBA) or GRK2 inhibition using paroxetine. Our findings suggest that GPR81 activation exerts a protective effect against myocardial I/R injury by enhancing glucose metabolism via the VILIP-1/GRK2/GLUT4 signaling axis.