Selective Pharmacological Blockade of GPR39 Markedly Reduces No Reflow and Infarct Volumes in a Rat Acute Myocardial Infarction When Administered Prior to Reperfusion

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Abstract Our aim was to determine whether selective pharmacological blockade of GPR39 by the novel drug, VC108, reduces no reflow (NRV) and infarct (INV) volumes during acute myocardial infarction (AMI). Immuocytochemistry and qPCR of isolated rat cardiac cells as well as immunohistochemistry and western blot of rat myocardium was performed for presence of GPR39. Rats underwent 1 h of coronary occlusion and 1 h of reperfusion. Groups 1 and 2 animals received drug/vehicle prior to or during coronary occlusion. Groups 3 and 4 received drug/vehicle 5 min prior to or 30 min after reperfusion. Readouts also included tissue pO 2 , hemodynamics, and wall thickening. In Groups 5 and 6 animals, drug was injected for measurement of plasma and tissue levels. Immunocytochemistry and qPCR of cells and immunohistochemistry and western blot of tissue revealed GPR39 expression in all cardiac cells analyzed as well as entire myocardial tissue. There was marked reduction in NRV and INV in groups 1 and 3 animals where both were measured and in Group 2 where INV was measured. In contrast, Group 4 animals failed to show reduction in NRV and INV with the drug. The reduction in NRV in all animals was associated with higher tissue pO 2 in VC108 compared to vehicle treated animals. Similar results were obtained for INV in only in Group 2 animals. In Group 3 animals direct cardiomyocyte effect of VC108 was seen in myocardium as evidenced by reduced necrosis and apoptosis. We conclude that VC108 is very effective in reducing INV and NRV in an AMI model when given before coronary occlusion or just prior to reperfusion (the latter being clinically more relevant) both in male and female rats. This effect is not seen after reperfusion. VC108 acts by blocking GPR39, resulting in vasodilation through pericyte and VSMC relaxation. It also directly protects cardiomyocytes by preventing downstream effects of GPR39 stimulation. New and Noteworthy GPR39 is the receptor for 15-HETE, which is a vasoconstrictor with direct cardiomyocyte detrimental effects. Pharmacological inhibition of GPR39 by a novel inhibitor, VC108, reduces coronary no reflow after acute myocardial infarction by relaxing contracted pericytes surrounding capillaries, whereby increasing oxygen delivery. GPR39 inhibition also reduces necrosis and ferroptosis by interrupting aberrant downstream signaling responsible for cell death. Hence, pharmacological inhibition of GPR39 by VC108 offers a novel treatment of acute myocardial infarction. Graphical Abstract Proposed mechanism of action of VC108 when given prior to and during coronary occlusion based on our results. The drug inhibits the action of the vasoconstrictor, 15-HETE, on GPR39. This causes vasodilation by relaxing contracted pericytes and increasing capillary perfusion, resulting in increased tissue pO 2 and reduction in no reflow (left side). When tissue pO 2 is not associated with necrosis, GPR39 inhibition by VC108 directly affects cardiomyocytes by inhibiting downstream signaling of GPR39 present in cardiomyocytes that can lead to cell injury and death. Hence, less necrosis and apoptosis are noted in VC108 versus vehicle treated animals. Created in https://BioRender.com .