Gαi2-mediated protection from ischaemic injury is modulated by endogenous RGS proteins in the mouse heart

Abstract

AimsRegulator of G protein signalling (RGS) proteins act as molecular 'off switches' that terminate G protein signalling by catalyzing the hydrolysis of Gα-bound GTP to GDP. Many different Gαi-coupled receptors have been implicated in the cardioprotective effects of ischaemic preconditioning. However, the role of RGS proteins in modulating cardioprotection has not been previously investigated. We used mice that were homozygous (GS/GS) or heterozygous (GS/) for a mutation in Gαi2 rendering it RGS-insensitive (G184S) to determine whether interactions between endogenous RGS proteins and Gαi2 modulate Gαi-mediated protection from ischaemic injury.Methods and resultsLangendorff-perfused mouse hearts were subjected to 30 min global ischaemia and 2 h reperfusion. Infarcts in GS/GS (14.5 of area at risk) and GS/ (22.6 of AAR) hearts were significantly smaller than those of / hearts (37.2 of AAR) and recovery of contractile function was significantly enhanced in GS/GS and GS/ hearts compared with / hearts. The cardioprotective phenotype was not reversed by wortmannin or U0126 but was reversed by 5-hydroxydecanoic acid and HMR 1098, indicating that RGS-insensitive Gαi2 protects the heart through a mechanism that requires functional ATP-dependent potassium channels but does not require acute activation of extracellular-regulated kinase or Akt signalling pathways.ConclusionsThis is the first study to demonstrate that Gαi2-mediated cardioprotection is suppressed by RGS proteins. These data suggest that RGS proteins may provide novel therapeutic targets to protect the heart from ischaemic injury. © 2011 The Author.