Protective effects of Gα_i3 deficiency in a murine heart-failure model of β₁-adrenoceptor overexpression

We have shown that in murine cardiomyopathy caused by overexpression of the β₁-adrenoceptor, Gα_i2-deficiency is detrimental. Given the growing evidence for isoform-specific Gα_i-functions, we now examined the consequences of Gα_i3 deficiency in the same heart-failure model. Mice overexpressing cardiac β₁-adrenoceptors with (β₁-tg) or without Gα_i3-expression (β₁-tg/Gα_i3^−/−) were compared to C57BL/6 wildtypes and global Gα_i3-knockouts (Gα_i3^−/−). The life span of β₁-tg mice was significantly shortened but improved when Gα_i3 was lacking (95% CI: 592–655 vs. 644–747 days). At 300 days of age, left-ventricular function and survival rate were similar in all groups. At 550 days of age, β₁-tg but not β₁-tg/Gα_i3^−/− mice displayed impaired ejection fraction (35 ± 18% vs. 52 ± 16%) compared to wildtype (59 ± 4%) and Gα_i3^−/− mice (60 ± 5%). Diastolic dysfunction of β₁-tg mice was prevented by Gα_i3 deficiency, too. The increase of ANP mRNA levels and ventricular fibrosis observed in β₁-tg hearts was significantly attenuated in β₁-tg/Gα_i3^−/− mice. Transcript levels of phospholamban, ryanodine receptor 2, and cardiac troponin I were similar in all groups. However, Western blots and phospho-proteomic analyses showed that in β₁-tg, but not β₁-tg/Gα_i3^−/− ventricles, phospholamban protein was reduced while its phosphorylation increased. Here, we show that in mice overexpressing the cardiac β₁-adrenoceptor, Gα_i3 deficiency slows or even prevents cardiomyopathy and increases shortened life span. Previously, we found Gα_i2 deficiency to aggravate cardiac dysfunction and mortality in the same heart-failure model. Our findings indicate isoform-specific interventions into G_i-dependent signaling to be promising cardio-protective strategies.