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

Technical Summary: Selective Pharmacological Blockade of GPR39 in Acute Myocardial Infarction

Problem Statement
Acute myocardial infarction (AMI) is frequently complicated by the "no-reflow" phenomenon (NRV), where microvascular obstruction prevents adequate tissue perfusion despite the restoration of epicardial coronary flow, leading to increased infarct volume (INV) and tissue damage. The study addresses the need for effective therapeutic strategies to mitigate NRV and reduce infarct size during AMI. Specifically, it investigates the role of the G-protein coupled receptor GPR39 as a potential therapeutic target and evaluates the efficacy of VC108, a novel selective pharmacological blocker of this receptor.

Methodology
The researchers utilized a rat model of AMI involving 1 hour of coronary occlusion followed by 1 hour of reperfusion. The experimental design included five distinct groups to evaluate the timing and impact of VC108 administration:

• Groups 1 & 2: Animals received VC108 or vehicle prior to or during coronary occlusion.
• Group 3: Animals received VC108 or vehicle 5 minutes prior to reperfusion.
• Groups 4 & 5: Animals received VC108 for the purpose of measuring plasma and tissue drug levels.

Physiological readouts included tissue partial pressure of oxygen (pO2), hemodynamics, and wall thickening. To establish the biological basis for the intervention, the study employed immunohistochemistry, western blotting, immunocytochemistry, and qPCR to detect GPR39 expression in rat myocardium and cardiac cells.

Key Results
The study yielded several critical findings regarding the efficacy of VC108 and the distribution of GPR39:

• Reduction in Pathology: There was a marked reduction in both no-reflow volume (NRV) and infarct volume (INV) in Groups 1 and 3, where both metrics were measured. Group 2 also demonstrated a significant reduction in INV.
• Physiological Correlation: The reduction in NRV across all treated animals correlated with higher tissue pO2 levels in the VC108 group compared to the vehicle group.
• Tissue Oxygenation vs. Infarct Size: While improved tissue oxygenation was consistently observed, the reduction in INV was not uniform across all groups; it was significant in Group 2 but not in Groups 1 and 3, despite the reduction in NRV in the latter.
• Receptor Expression: A novel finding revealed high expression of GPR39 in cardiomyocytes, identified through immunohistochemistry, western blot, immunocytochemistry, and qPCR. This represents a previously unknown localization of the receptor.

Mechanism of Action
The authors conclude that VC108 exerts its protective effects through two primary mechanisms:

1. Vasodilation: By blocking GPR39, VC108 relaxes pericytes and vascular smooth muscle cells (VSMCs), thereby improving microvascular flow and tissue oxygenation.
2. Direct Cardioprotection: The drug directly protects cardiomyocytes by preventing the downstream effects of GPR39 stimulation.

Significance and Claims
The paper claims that selective pharmacological blockade of GPR39 by VC108 is highly effective in reducing both no-reflow and infarct volumes in a rat model of AMI. The efficacy is demonstrated when the drug is administered either before coronary occlusion or immediately prior to reperfusion. The study highlights the dual benefit of this approach: improving microvascular perfusion via vasodilation and providing direct cellular protection to cardiomyocytes. The identification of high GPR39 expression in cardiomyocytes is presented as a hitherto unknown finding that underpins the direct protective mechanism of the drug.