| First Author | Streit MR | Year | 2016 |
| Journal | PLoS One | Volume | 11 |
| Issue | 1 | Pages | e0146988 |
| PubMed ID | 26811901 | Mgi Jnum | J:252431 |
| Mgi Id | MGI:6093348 | Doi | 10.1371/journal.pone.0146988 |
| Citation | Streit MR, et al. (2016) Cardiac Effects of Attenuating Gsalpha - Dependent Signaling. PLoS One 11(1):e0146988 |
| abstractText | AIMS: Inhibition of beta-adrenergic signalling plays a key role in treatment of heart failure. Gsalpha is essential for beta-adrenergic signal transduction. In order to reduce side-effects of beta-adrenergic inhibition diminishing beta-adrenergic signalling in the heart at the level of Gsalpha is a promising option. METHODS AND RESULTS: We analyzed the influence of Gsalpha on regulation of myocardial function and development of cardiac hypertrophy, using a transgenic mouse model (C57BL6/J mice) overexpressing a dominant negative Gsalpha-mutant under control of the alpha-MHC-promotor. Cardiac phenotype was characterized in vivo and in vitro and under acute and chronic beta-adrenergic stimulation. At rest, Gsalpha-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. beta-blockade by propranolol revealed no baseline differences of hemodynamic parameters between wildtype and Gsalpha-DN-mice. Acute adrenergic stimulation resulted in decreased beta-adrenergic responsiveness in Gsalpha-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 Gsalpha-DN-mice after chronic isoproterenol stimulation. CONCLUSION: Overexpression of a dominant negative mutant of Gsalpha leads to decreased beta-adrenergic responsiveness and is protective against isoproterenol-induced hypertrophy. Thus, Gsalpha-DN-mice provide novel insights into beta-adrenergic signal transduction and its modulation in myocardial overload and failure. |
