Gα(i2)- and Gα(i3)-Deficient Mice Display Opposite Severity of Myocardial Ischemia Reperfusion Injury

G-protein-coupled receptors (GPCRs) are the most abundant receptors in the heart and therefore are common targets for cardiovascular therapeutics. The activated GPCRs transduce their signals via heterotrimeric G-proteins. The four major families of G-proteins identified so far are specified through their α-subunit: Gα(i), Gα(s), Gα(q) and G(12/13). Gα(i)-proteins have been reported to protect hearts from ischemia reperfusion injury. However, determining the individual impact of Gα(i2) or Gα(i3) on myocardial ischemia injury has not been clarified yet. Here, we first investigated expression of Gα(i2) and Gα(i3) on transcriptional level by quantitative PCR and on protein level by immunoblot analysis as well as by immunofluorescence in cardiac tissues of wild-type, Gα(i2)-, and Gα(i3)-deficient mice. Gα(i2) was expressed at higher levels than Gα(i3) in murine hearts, and irrespective of the isoform being knocked out we observed an up regulation of the remaining Gα(i)-protein. Myocardial ischemia promptly regulated cardiac mRNA and with a slight delay protein levels of both Gα(i2) and Gα(i3), indicating important roles for both Gα(i) isoforms. Furthermore, ischemia reperfusion injury in Gα(i2)- and Gα(i3)-deficient mice exhibited opposite outcomes. Whereas the absence of Gα(i2) significantly increased the infarct size in the heart, the absence of Gα(i3) or the concomitant upregulation of Gα(i2) dramatically reduced cardiac infarction. In conclusion, we demonstrate for the first time that the genetic ablation of Gα(i) proteins has protective or deleterious effects on cardiac ischemia reperfusion injury depending on the isoform being absent.