bioRxiv Science⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.64898/2026.01.16.699339

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

Methner, C.·Le, D. E.·Liu, L.·Plascencia, M.·Kajimoto, M.·thompson, a.·Cianciulli, A.·Pellacani, A.·Micheli, F.·Kaul, S.
View original source ↗Export metadata ↓

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 pO2, 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 pO2 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 NoteworthyGPR39 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 AbstractProposed 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 pO2 and reduction in no reflow (left side). When tissue pO2 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. O_FIG O_LINKSMALLFIG WIDTH=137 HEIGHT=200 SRC="FIGDIR/small/699339v2_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@1058995org.highwire.dtl.DTLVardef@8bc0ceorg.highwire.dtl.DTLVardef@11f44e0org.highwire.dtl.DTLVardef@1e2e337_HPS_FORMAT_FIGEXP M_FIG C_FIG

Explore related subjects

physiologyPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Methner, C., Le, D. E., Liu, L., Plascencia, M., Kajimoto, M., thompson, a., Cianciulli, A., Pellacani, A., Micheli, F., Kaul, S.. 2026-01-20. Selective Pharmacological Blockade of GPR39 Markedly Reduces No Reflow and Infarct Volumes in a Rat Model of Acute Myocardial Infarction. https://doi.org/10.64898/2026.01.16.699339

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Hypothalamic Farnesoid X Receptor deficiency alters energy balance by modulating hepatic glucose production and adipose tissue metabolism through central insulin signaling.

Objectives: The bile acid nuclear receptor Farnesoid X Receptor (FXR, NR1H4) is a major regulator of metabolism and energy homeostasis in peripheral organs. It modulates bile acid, glucose, and lipid metabolism, as well as fat mass and body weight. However, FXR is also expressed in the brain, particularly in the hypothalamus, a key center for the regulation of energy homeostasis. Although one study has demonstrated a role for brain FXR activation in energy balance, its specific hypothalamic role is still unknown. Here, we examined the role of FXR in the mediobasal hypothalamus in the regulation of energy balance. Methods: We used a genetic approach combined with metabolic phenotyping to determine the effect of FXR invalidation in the mediobasal hypothalamus on metabolic parameters involved in the central regulation of energy homeostasis. Results: Our results demonstrate that hypothalamic FXR deficiency induces a positive energy balance, resulting in a reduction in energy expenditure due to alterations in glucose metabolism accompanied by structural changes in white adipose tissues. Conclusion: This study uncovers a previously unrecognized role for hypothalamic FXR in the central homeostatic control of energy balance, providing new insights into its contribution to peripheral glucose metabolism and adipose tissue structural remodeling.

physiology↗
bioRxiv2026

Rad and Phospholamban are Key Drivers of the Ventricular Adrenergic Response and Stress-Induced Arrhythmia

The adrenergic response is a fundamental mechanism that regulates heart rate (chronotropy), cardiac contractility (inotropy) and relaxation (lusitropy). Adrenergic stress is also a recognized trigger of arrhythmia in disease. Yet, our understanding of the underlying molecular basis remains incomplete. Protein kinase A (PKA) and the calcium/calmodulin-dependent kinase II (CaMKII) phosphorylate multiple targets proposed to participate in the adrenergic response, including the GTP-binding protein Rad, phospholamban (PLB) and ryanodine receptor 2 (RyR2). Here we demonstrate that phosphorylation of both Rad and PLB is necessary for inotropy and lusitropy. We show that changes in cardiac contractility and relaxation are primarily dependent on intracellular calcium handling. Finally, we report that Rad and PLB control stress-induced arrhythmogenesis, despite the phosphorylation of other pro-arrhythmic targets. We have identified the essential molecular components of the adrenergic response, resolving a long-standing debate in cardiac excitation-contraction coupling and refining current models of sympathetic regulation in health and disease.

physiology↗
bioRxiv2026

Light-cycle time-restricted feeding remodels a hidden layer of the cardiac transcriptome through sex-specific transcript switching

Light-cycle time-restricted feeding disrupts daily cardiovascular and thermoregulatory rhythms, but the molecular effects of light-cycle time-restricted feeding on the heart have been measured only at the level of total gene expression. We used Oxford Nanopore long-read RNA sequencing to resolve the full-length ventricular transcriptome from male and female mice under ad libitum feeding or light-cycle time-restricted feeding across the 24-hour cycle. Greater than 20% of cardiac transcripts represent unannotated variants of known genes absent from the current GENCODE reference annotation. Light-cycle time-restricted feeding reorganizes transcript usage across hundreds of genes, including genes encoding splicing regulators, largely without changing total gene expression. The genes affected are sex-specific, with fewer than 2% of changes shared at the gene, transcript, and transcript-usage levels. We show that transcript-level regulation is a previously underrecognized component of the cardiac response to altered feeding behavior, undetected by conventional short-read approaches.

physiology↗