Cardiac effects of attenuating Gsα

• Verfasst von: Streit, Marcus R. [VerfasserIn]
• Verfasst von: Weiss, Celine [VerfasserIn]
• Verfasst von: Meyer, Sören [VerfasserIn]
• Verfasst von: Ochs, Marco [VerfasserIn]
• Verfasst von: Hagenmüller, Marco [VerfasserIn]
• Verfasst von: Riffel, Johannes [VerfasserIn]
• Verfasst von: Buß, Sebastian Johannes [VerfasserIn]
• Verfasst von: Heger, Thomas [VerfasserIn]
• Verfasst von: Katus, Hugo [VerfasserIn]
• Verfasst von: Hardt, Stefan [VerfasserIn]
• Titel: Cardiac effects of attenuating Gsα
• Titelzusatz: dependent signaling
• Verf.angabe: Marcus R. Streit, Celine S. Weiss, Sören Meyer, Marco M. Ochs, Marco Hagenmueller, Johannes H. Riffel, Sebastian J. Buss, Thomas Heger, Hugo A. Katus, Stefan E. Hardt
• E-Jahr: 2016
• Jahr: January 26, 2016
• Umfang: 19 S.
• Fussnoten: Im Text wird alpha als griechischer Buchstabe dargestellt ; Gesehen am 20.05.2020
• Titel Quelle: Enthalten in: PLOS ONE
• Ort Quelle: San Francisco, California, US : PLOS, 2006
• Jahr Quelle: 2016
• Band/Heft Quelle: 11(2016,1) Artikel-Nummer e0146988, 19 Seiten
• ISSN Quelle: 1932-6203
• DOI: doi:10.1371/journal.pone.0146988
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: G-protein signaling
• Sach-SW: Genetically modified animals
• Sach-SW: Heart
• Sach-SW: Heart failure
• Sach-SW: Heart rate
• Sach-SW: Hyperexpression techniques
• Sach-SW: Isoproterenol
• Sach-SW: Mouse models
• K10plus-PPN: 1698605226

Abstract

Aims 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. Methods and Results We analyzed the influence of Gsα on regulation of myocardial function and development of cardiac hypertrophy, using a transgenic mouse model (C57BL6/J mice) overexpressing a dominant negative Gsα-mutant under control of the α-MHC-promotor. Cardiac phenotype was characterized in vivo and in vitro and under acute and chronic β-adrenergic stimulation. At rest, Gsα-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. β-blockade by propranolol revealed no baseline differences of hemodynamic parameters between wildtype and Gsα-DN-mice. Acute adrenergic stimulation resulted in decreased β-adrenergic responsiveness in Gsα-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 Gsα-DN-mice after chronic isoproterenol stimulation. Conclusion Overexpression of a dominant negative mutant of Gsα leads to decreased β-adrenergic responsiveness and is protective against isoproterenol-induced hypertrophy. Thus, Gsα-DN-mice provide novel insights into β-adrenergic signal transduction and its modulation in myocardial overload and failure.