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

We have shown that in murine cardiomyopathy caused by overexpression of the β-adrenoceptor, Gα-deficiency is detrimental. Given the growing evidence for isoform-specific Gα-functions, we now examined the consequences of Gα deficiency in the same heart-failure model. Mice overexpressing cardiac β-adrenoceptors with (β-tg) or without Gα-expression (β-tg/Gα) were compared to C57BL/6 wildtypes and global Gα-knockouts (Gα). The life span of β-tg mice was significantly shortened but improved when Gα 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-tg but not β-tg/Gα mice displayed impaired ejection fraction (35 ± 18% vs. 52 ± 16%) compared to wildtype (59 ± 4%) and Gα mice (60 ± 5%). Diastolic dysfunction of β-tg mice was prevented by Gα deficiency, too. The increase of ANP mRNA levels and ventricular fibrosis observed in β-tg hearts was significantly attenuated in β-tg/Gα 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-tg, but not β-tg/Gα ventricles, phospholamban protein was reduced while its phosphorylation increased. Here, we show that in mice overexpressing the cardiac β-adrenoceptor, Gα deficiency slows or even prevents cardiomyopathy and increases shortened life span. Previously, we found Gα deficiency to aggravate cardiac dysfunction and mortality in the same heart-failure model. Our findings indicate isoform-specific interventions into G-dependent signaling to be promising cardio-protective strategies.