Selective Pharmacological Blockade of GPR39 Markedly Reduces No Reflow and Infarct Volumes in a Rat Model of Acute Myocardial Infarction

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 acute myocardial infarction (AMI). 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. Group 3 received drug/vehicle 5 min prior to reperfusion. Readouts also included tissue pO2, hemodynamics, and wall thickening. In Groups 4 and 5 animals, drug was injected for measurement of plasma and tissue levels. Immunohistochemistry and western blot of rat myocardium as well as immuocytochemistry and qPCR of cardiac cells was performed for presence of GPR39. 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. The reduction in NRV in all animals was associated with higher tissue pO2 during VC108 compared to vehicle. Similar results were obtained for INV in Group 2 animal, but not in Groups 1 and 3. Immunohistochemistry and western blot of heart tissue as well as immunocytochemistry and qPCR of cells revealed high expression of GPR39 in cardiomyocytes, a hithertofore unknown finding. We conclude that VC108 is very effective in reducing INV and NRV in a rat AMI model when given before coronary occlusion or just prior to reperfusion. VC108 acts by blocking GPR39, resulting in vasodilation by relaxing pericytes and VSMCs. It also directly protects cardiomyocytes by preventing downstream effects of GPR39 stimulation. Competing Interest Statement Oregon Health & Science University and Vasocardea, Inc. have a joint patent application filed globally (WO2021222858 and corresponding national filings) that encompasses drugs that inhibit GPR39. Vasocardea, Inc. has an additional patent application filed globally (WO2023076219 and corresponding national filings) that encompasses VC108. Vasocardea, Inc. has exclusive rights to develop and commercialize drugs under all of these patent applications. Aptuit/Evotec has assigned all patent rights to Oregon Health & Science University and Vasocardea, Inc. Dr. Kaul is the founder and President of Vasocardea, Inc., a Delaware incorporated company located in Portland, Oregon. The information in this manuscript does not represent the views of the Veterans Administration or the US government. Footnotes Supported, in part, by grants from the Garthe and Grace L. Brown Fund and the John E. and Robin Jaqua Fund at the Oregon Community Foundation and by the Ernest C. Swigert Endowment at the Oregon Health & Science University Presented in part at the Annual Scientific Session of the American Heart Association, in November 2023 in Philadelphia, USA and will also be presented in part at the Annual Scientific Session of the American Heart Association in November 2025 in New Orleans, USA Acronyms and Abbreviations - 15-HETE - 15-hydroxyeicosatetraenoic acid - 14,15-EET - 14,15-epoxyeicosatrienoic acid - AMI - acute myocardial infarction - GPR39 - G-protein coupled receptor 39 - IHC - immunohistochemistry - INV - infarct volume - IRV - ischemic risk volume - LC - left coronary - LV - left ventricular - NRV - no reflow volume - qPCR - quantitative polymerase chain reaction - RNA - ribonucleic acid - TTC - 1% 2,3,5 triphenyl tetrazolium chloride - VSMC(s) - vascular smooth muscle cell(s) - WT - wall thickening