Protective effects of Gα i3 deficiency in a murine heart-failure model of β 1 -adrenoceptor overexpression

We have shown that in murine cardiomyopathy caused by overexpression of the β 1 -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 β 1 -adrenoceptors with (β 1 -tg) or without Gα i3 -expression (β 1 -tg/Gα i3 −/− ) were compared to C57BL/6 wildtypes and global Gα i3 -knockouts (Gα i3 −/− ). The life span of β 1 -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, β 1 -tg but not β 1 -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 β 1 -tg mice was prevented by Gα i3 deficiency, too. The increase of ANP mRNA levels and ventricular fibrosis observed in β 1 -tg hearts was significantly attenuated in β 1 -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 β 1 -tg, but not β 1 -tg/Gα i3 −/− ventricles, phospholamban protein was reduced while its phosphorylation increased. Here, we show that in mice overexpressing the cardiac β 1 -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.