Abstract 391: Cardiac Effects of Attenuating Gsα- dependent Signaling
Background: Inhibition of β-adrenergic signaling plays a key role in treatment of heart failure. GSα (excitatory subunit of Gα-protein) is essential for β-adrenergic signal transduction. Transgenic mice overexpressing GSα develop cardiomyopathy. Several lines of evidence suggest additional roles of GSα-signaling beyond the β-adrenergic system.
Methods: In this study we analyzed the influence of GSα on regulation of myocardial function and development of cardiac hypertrophy, using a transgenic mouse model overexpressing a dominant negative GSα-mutant (70% cAMP reduction) under control of the α-MHC-promotor. Cardiac phenotype was characterized in vivo and in vitro. Response to acute (isoproterenol 0,02– 0,2 μg×kg−1×min−1 i.v.) and chronic (isoproterenol 30 μg×g−1×d−1 s.c., 14d) β-adrenergic stimulation was analyzed.
Results: At rest, GSα-DN-mice showed bradycardia (602±17 vs. 660±13 bpm, p<0.01) and decreased dp/dtmax (5143±462 vs. 7194±267 mmHg/s, p<0.003). 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 decreasedβ-adrenergic responsiveness in GSα-DN-mice. Under chronic adrenergic stimulation wildtype mice developed myocardial hypertrophy associated with increase of LV/BW-ratio by 17% (4.1±0.2 vs. 3.5±0.1 mg/g, p<0.03) and increase of cardiac myocyte size by 24% (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 are a suitable model for characterization of β-adrenergic signal transduction in heart failure and for evaluation of potential prevention points for contractile dysfunction.