Inhibition of Gαi2 – RGS Protein Interactions Protects the Heart from Ischemic Injury

Signaling through Gαi‐coupled receptors protects the heart from ischemic injury. The activity of Gαi is modulated by regulator of G protein signaling (RGS) proteins that terminate Gαi signaling by catalyzing the hydrolysis of Gαi‐bound GTP. We used knock‐in mice in which interactions between Gαi2 and RGS proteins are disrupted by a Gαi2G184S (GS) point mutation to determine whether interactions between Gαi2 and endogenous RGS proteins modulate Gαi‐mediated protection from ischemic injury. Hearts isolated from wildtype (+/+) mice and mice homozygous (GS/GS) or heterozygous (GS/+) for Gαi2G184S were subjected to 30 minutes ischemia and 2 hours reperfusion using the Langendorff method. Infarcts in GS/GS and GS/+ hearts were significantly smaller than those of +/+ hearts. Expression of Gαi2G184S had no effect on preischemic contractile function. However, postischemic recovery of contractile function was significantly enhanced in GS/GS and GS/+ hearts compared to +/+ hearts. The cardioprotective phenotype of GS/+ and GS/GS hearts was reversed by 5‐hydroxydecanoate indicating that inhibition of RGS‐ Gαi2 interactions protects the heart through a mechanism that requires mitochondrial K+ATP channels. These data suggest that RGS proteins may provide novel therapeutic targets to protect the heart from ischemic injury. (Supported by NIH R01 GM39561; AFPE, and the Bower, Bennet and Bennet Endowed Research Award).