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

ABSTRACT: 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.

SUBMITTER: Schroper T

PROVIDER: S-EPMC10933181 | biostudies-literature | 2024 Apr

REPOSITORIES: biostudies-literature

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

Schröper Tobias T Mehrkens Dennis D Leiss Veronika V Tellkamp Frederik F Engelhardt Stefan S Herzig Stefan S Birnbaumer Lutz L Nürnberg Bernd B Matthes Jan J

Naunyn-Schmiedeberg's archives of pharmacology 20231016 4

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 ...[more]

PMID: 37843590

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Project description:AimsChronic heart failure (CHF) can be caused by autoantibodies stimulating the heart via binding to first and/or second extracellular loops of cardiac β1 -adrenoceptors. Allosteric receptor activation depends on conformational features of the autoantibody binding site. Elucidating these features will pave the way for the development of specific diagnostics and therapeutics. Our aim was (i) to fine-map the conformational epitope within the second extracellular loop of the human β1 -adrenoceptor (β1 ECII ) that is targeted by stimulating β1 -receptor (auto)antibodies and (ii) to generate competitive cyclopeptide inhibitors of allosteric receptor activation, which faithfully conserve the conformational auto-epitope.Methods and resultsNon-conserved amino acids within the β1 ECII loop (compared with the amino acids constituting the ECII loop of the β2 -adrenoceptor) were one by one replaced with alanine; potential intra-loop disulfide bridges were probed by cysteine-serine exchanges. Effects on antibody binding and allosteric receptor activation were assessed (i) by (auto)antibody neutralization using cyclopeptides mimicking β1 ECII ± the above replacements, and (ii) by (auto)antibody stimulation of human β1 -adrenoceptors bearing corresponding point mutations. With the use of stimulating β1 -receptor (auto)antibodies raised in mice, rats, or rabbits and isolated from exemplary dilated cardiomyopathy patients, our series of experiments unmasked two features of the β1 ECII loop essential for (auto)antibody binding and allosteric receptor activation: (i) the NDPK211-214 motif and (ii) the intra-loop disulfide bond C209 ↔C215 . Of note, aberrant intra-loop disulfide bond C209 ↔C216 almost fully disrupted the functional auto-epitope in cyclopeptides.ConclusionsThe conformational auto-epitope targeted by cardio-pathogenic β1 -receptor autoantibodies is faithfully conserved in cyclopeptide homologues of the β1 ECII loop bearing the NDPK211-214 motif and the C209 ↔C215 bridge while lacking cysteine C216 . Such molecules provide promising tools for novel diagnostic and therapeutic approaches in β1 -autoantibody-positive CHF.

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

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Protective effects of Gα<sub>i3</sub> deficiency in a murine heart-failure model of β<sub>1</sub>-adrenoceptor overexpression.

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Dataset Information

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

Publications

Protective effects of Gα&lt;sub&gt;i3&lt;/sub&gt; deficiency in a murine heart-failure model of β&lt;sub&gt;1&lt;/sub&gt;-adrenoceptor overexpression.

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OmicsDI is part of the ELIXIR infrastructure

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

Protective effects of Gα<sub>i3</sub> deficiency in a murine heart-failure model of β<sub>1</sub>-adrenoceptor overexpression.