Abstract 4357639: Reduction in Myocardial Infarct Size by GPR39 Inhibition Maybe Related to its Direct Tissue Effects

Background: We previously demonstrated that GPR39 is present in vascular smooth muscle cells (VSMCs) and pericytes in cardiac tissue. We also showed that genetic deletion of GPR39 reduces infarct size in a rodent acute myocardial infarction model. Here we investigated whether selective pharmacological blockade of GPR39 by VC108 reduces myocardial infarct size by increasing blood flow. Methods: Rats were administered 0.5 mg/kg of VC108 intravenously, a dose that occupies >90% of receptors in the body. Tissue pO 2 was measured, followed by 1 h of coronary occlusion and 1 h of reperfusion. At 30 min each into occlusion and reperfusion tissue pO 2 was again measured. After euthanasia, infarct volume from multiple heart slices was measured using triphenyl tetrazolium chloride. From separate rats, whole heart tissue, cardiomyocytes, pericytes, and VSMCs were isolated for qPCR. Isolated cardiomyocytes also underwent immunocytochemistry (ICC) for presence of GPR39 and cardiac tissue was subjected to immunohistochemistry (IHC) for the same. Results: Figure 1 illustrates markedly smaller infarct volume in VC108 (A) versus vehicle treated (B) animals. Aggregate data from 27 animals demonstrate the same (C). However, tissue pO 2 levels were not associated with infarct volume reduction implying a direct tissue effect of GPR39 inhibition not attributable to vasodilation. ICC revealed presence of GPR39 in a cardiomyocyte (Figure 2A). IHC showed co-localization of GPR39 in pericytes, VSMCs, and cardiomyocytes (Figure 2C). qPCR revealed GPR39 presence in cardiomyocytes equivalent to that of VSMCs, which has not been described before. Conclusions: The marked reduction in infarct volume noted in VC108 treated animals is not associated with increases in tissue pO 2 during coronary occlusion, indicating a flow-independent mechanism of cardioprotection. Here we show that cardiomyocytes possess GPR39, which is a new finding. Inhibition of downstream signaling from GPR39 may reduce infarction by preventing ferroptosis, apoptosis and/or necrosis.