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G?(i2)-mediated protection from ischaemic injury is modulated by endogenous RGS proteins in the mouse heart.

ABSTRACT:

Aims

Regulator of G protein signalling (RGS) proteins act as molecular 'off switches' that terminate G protein signalling by catalyzing the hydrolysis of G?-bound GTP to GDP. Many different G?(i)-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 G?(i2) rendering it RGS-insensitive (G184S) to determine whether interactions between endogenous RGS proteins and G?(i2) modulate G?(i)-mediated protection from ischaemic injury.

Methods and results

Langendorff-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 G?(i2) 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.

Conclusions

This is the first study to demonstrate that G?(i2)-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.

SUBMITTER: Waterson RE

PROVIDER: S-EPMC3112020 | biostudies-literature | 2011 Jul

REPOSITORIES: biostudies-literature

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Gα(i2)-mediated protection from ischaemic injury is modulated by endogenous RGS proteins in the mouse heart.

Waterson Rachael E RE Thompson Corbin G CG Mabe Nathaniel W NW Kaur Kuljeet K Talbot Jeffery N JN Neubig Richard R RR Rorabaugh Boyd R BR

Cardiovascular research 20110223 1

<h4>Aims</h4>Regulator 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 Gα(i)-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 Gα(i2) re ...[more]

PMID: 21349876

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