Pharmacologic ROMK Inhibition Protects Against Myocardial Ischemia Reperfusion Injury

TL;DR

Inhibiting the ROMK channel in heart cells protects mice from heart damage during blood flow restoration after a heart attack.

Contribution

Pharmacologic inhibition of ROMK, not germline knockout, reveals protective effects against myocardial ischemia reperfusion injury.

Findings

ROMK inhibition protects mouse hearts from ischemia reperfusion injury.

ROMK inhibition increases mitochondrial uncoupling and ROS production.

ROMK inhibition promotes mitochondrial swelling in the absence of ATP.

Abstract

Mitochondrial ATP-sensitive K+ channels are closely linked to cardioprotection and are potential therapeutic targets during ischemia reperfusion (IR) injury. The renal outer medullary K+ channel isoform 2 (ROMK2) is an ATP-sensitive K+ channel found in the mitochondria of cardiomyocytes. While the germline knockout of ROMK does not mediate myocardial IR injury, the effect of ROMK loss of function on IR injury in the adult myocardium is unknown. By using a selective small molecule inhibitor of ROMK, we paradoxically found that mouse hearts were protected from IR injury after ROMK inhibition compared to vehicle-treated animals. In addition, we found that ROMK inhibition leads to exaggerated mitochondrial uncoupling and increased ROS production. Phosphatidylinositol 4,5-bisphosphate (PIP2), an activator of ROMK, increased the effect of ATP to hyperpolarize cardiac mitochondrial membrane potential. ROMK inhibition also increased mitochondrial swelling in the absence of ATP. In conclusion, pharmacologic ROMK inhibition protects the murine heart from IR injury and may promote a phenotype of enhanced mitochondrial matrix K+. ROMK may be more important during conditions that promote mitochondrial matrix K+ efflux than influx. Further research to understand its role in mitochondrial K+ handling and as a therapeutic target in IR injury is needed.

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