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Cardiac Effects of Attenuating Gs? - Dependent Signaling.

ABSTRACT: Inhibition of ?-adrenergic signalling plays a key role in treatment of heart failure. Gs? is essential for ?-adrenergic signal transduction. In order to reduce side-effects of beta-adrenergic inhibition diminishing ?-adrenergic signalling in the heart at the level of Gs? is a promising option.We analyzed the influence of Gs? on regulation of myocardial function and development of cardiac hypertrophy, using a transgenic mouse model (C57BL6/J mice) overexpressing a dominant negative Gs?-mutant under control of the ?-MHC-promotor. Cardiac phenotype was characterized in vivo and in vitro and under acute and chronic ?-adrenergic stimulation. At rest, Gs?-DN-mice showed bradycardia (602 ± 13 vs. 660 ± 17 bpm, p<0.05) and decreased dp/dtmax (5037 ± 546- vs. 6835 ± 505 mmHg/s, p = 0.02). No significant differences were found regarding ejection fraction, heart weight and cardiomyocyte size. ?-blockade by propranolol revealed no baseline differences of hemodynamic parameters between wildtype and Gs?-DN-mice. Acute adrenergic stimulation resulted in decreased ?-adrenergic responsiveness in Gs?-DN-mice. Under chronic adrenergic stimulation, wildtype mice developed myocardial hypertrophy associated with increase of LV/BW-ratio by 23% (4.4 ± 0.2 vs. 3.5 ± 0.1 mg/g, p<0.01) and cardiac myocyte size by 24% (14927 ± 442 px vs. 12013 ± 583 px, p<0.001). In contrast, both parameters were unchanged in Gs?-DN-mice after chronic isoproterenol stimulation.Overexpression of a dominant negative mutant of Gs? leads to decreased ?-adrenergic responsiveness and is protective against isoproterenol-induced hypertrophy. Thus, Gs?-DN-mice provide novel insights into ?-adrenergic signal transduction and its modulation in myocardial overload and failure.

SUBMITTER: Streit MR

PROVIDER: S-EPMC4727906 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Cardiac Effects of Attenuating Gsα - Dependent Signaling.

Streit Marcus R MR Weiss Celine S CS Meyer Sören S Ochs Marco M MM Hagenmueller Marco M Riffel Johannes H JH Buss Sebastian J SJ Heger Thomas T Katus Hugo A HA Hardt Stefan E SE

PloS one 20160126 1

<h4>Aims</h4>Inhibition of β-adrenergic signalling plays a key role in treatment of heart failure. Gsα is essential for β-adrenergic signal transduction. In order to reduce side-effects of beta-adrenergic inhibition diminishing β-adrenergic signalling in the heart at the level of Gsα is a promising option.<h4>Methods and results</h4>We analyzed the influence of Gsα on regulation of myocardial function and development of cardiac hypertrophy, using a transgenic mouse model (C57BL6/J mice) overexpr ...[more]

PMID: 26811901

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Cardiac Effects of Attenuating Gs? - Dependent Signaling.

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Cardiac Effects of Attenuating Gsα - Dependent Signaling.

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