Protective effects of Gαi3 deficiency in a murine heart-failure model of β1-adrenoceptor overexpression.

Tobias Schröper, Dennis Mehrkens, Veronika Leiss, Frederik Tellkamp, Stefan Engelhardt, Stefan Herzig, Lutz Birnbaumer, Bernd Nürnberg, Jan Matthes

Naunyn-Schmiedeberg's archives of pharmacology 2024 Apr

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We have shown that in murine cardiomyopathy caused by overexpression of the β1-adrenoceptor, Gαi2-deficiency is detrimental. Given the growing evidence for isoform-specific Gαi-functions, we now examined the consequences of Gαi3 deficiency in the same heart-failure model. Mice overexpressing cardiac β1-adrenoceptors with (β1-tg) or without Gαi3-expression (β1-tg/Gαi3-/-) were compared to C57BL/6 wildtypes and global Gαi3-knockouts (Gαi3-/-). The life span of β1-tg mice was significantly shortened but improved when Gαi3 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/Gαi3-/- mice displayed impaired ejection fraction (35 ± 18% vs. 52 ± 16%) compared to wildtype (59 ± 4%) and Gαi3-/- mice (60 ± 5%). Diastolic dysfunction of β1-tg mice was prevented by Gαi3 deficiency, too. The increase of ANP mRNA levels and ventricular fibrosis observed in β1-tg hearts was significantly attenuated in β1-tg/Gαi3-/- 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/Gαi3-/- ventricles, phospholamban protein was reduced while its phosphorylation increased. Here, we show that in mice overexpressing the cardiac β1-adrenoceptor, Gαi3 deficiency slows or even prevents cardiomyopathy and increases shortened life span. Previously, we found Gαi2 deficiency to aggravate cardiac dysfunction and mortality in the same heart-failure model. Our findings indicate isoform-specific interventions into Gi-dependent signaling to be promising cardio-protective strategies. © 2023. The Author(s).

Citation

Tobias Schröper, Dennis Mehrkens, Veronika Leiss, Frederik Tellkamp, Stefan Engelhardt, Stefan Herzig, Lutz Birnbaumer, Bernd Nürnberg, Jan Matthes. Protective effects of Gαi3 deficiency in a murine heart-failure model of β1-adrenoceptor overexpression. Naunyn-Schmiedeberg's archives of pharmacology. 2024 Apr;397(4):2401-2420