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Protective effects of Gαi3 deficiency in a murine heart-failure model of β1-adrenoceptor overexpression.
- Source :
- Naunyn-Schmiedeberg's Archives of Pharmacology; Apr2024, Vol. 397 Issue 4, p2401-2420, 20p
- Publication Year :
- 2024
-
Abstract
- We have shown that in murine cardiomyopathy caused by overexpression of the β<subscript>1</subscript>-adrenoceptor, Gα<subscript>i2</subscript>-deficiency is detrimental. Given the growing evidence for isoform-specific Gα<subscript>i</subscript>-functions, we now examined the consequences of Gα<subscript>i3</subscript> deficiency in the same heart-failure model. Mice overexpressing cardiac β<subscript>1</subscript>-adrenoceptors with (β<subscript>1</subscript>-tg) or without Gα<subscript>i3</subscript>-expression (β<subscript>1</subscript>-tg/Gα<subscript>i3</subscript><superscript>−/−</superscript>) were compared to C57BL/6 wildtypes and global Gα<subscript>i3</subscript>-knockouts (Gα<subscript>i3</subscript><superscript>−/−</superscript>). The life span of β<subscript>1</subscript>-tg mice was significantly shortened but improved when Gα<subscript>i3</subscript> 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<subscript>1</subscript>-tg but not β<subscript>1</subscript>-tg/Gα<subscript>i3</subscript><superscript>−/−</superscript> mice displayed impaired ejection fraction (35 ± 18% vs. 52 ± 16%) compared to wildtype (59 ± 4%) and Gα<subscript>i3</subscript><superscript>−/−</superscript> mice (60 ± 5%). Diastolic dysfunction of β<subscript>1</subscript>-tg mice was prevented by Gα<subscript>i3</subscript> deficiency, too. The increase of ANP mRNA levels and ventricular fibrosis observed in β<subscript>1</subscript>-tg hearts was significantly attenuated in β<subscript>1</subscript>-tg/Gα<subscript>i3</subscript><superscript>−/−</superscript> 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<subscript>1</subscript>-tg, but not β<subscript>1</subscript>-tg/Gα<subscript>i3</subscript><superscript>−/−</superscript> ventricles, phospholamban protein was reduced while its phosphorylation increased. Here, we show that in mice overexpressing the cardiac β<subscript>1</subscript>-adrenoceptor, Gα<subscript>i3</subscript> deficiency slows or even prevents cardiomyopathy and increases shortened life span. Previously, we found Gα<subscript>i2</subscript> deficiency to aggravate cardiac dysfunction and mortality in the same heart-failure model. Our findings indicate isoform-specific interventions into G<subscript>i</subscript>-dependent signaling to be promising cardio-protective strategies. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 00281298
- Volume :
- 397
- Issue :
- 4
- Database :
- Complementary Index
- Journal :
- Naunyn-Schmiedeberg's Archives of Pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 176005759
- Full Text :
- https://doi.org/10.1007/s00210-023-02751-8