Overexpressed cardiac Gsα in rabbits

We overexpressed cardiac Gsα in rabbits using the β-myosin heavy chain promoter. Gsα protein levels in the heart were increased 3-fold by Western blotting in both juvenile (3–4 months), adult (8–10 months), and older (11–16 months) rabbits, compared with wild type (WT) littermates. In transgenic (TG) rabbits, baseline levels of heart rate were elevated, P < 0.05 (268 ± 17 vs. 209 ± 15 beats/min), as well as left ventricular (LV) contractility (LV dP/dt 5475 ± 482 vs. 3740 ± 246 mm Hg/s). These values and LV ejection fraction remained significantly elevated in older TG rabbits (11–16 months). However, maximal levels of LV dP/dt and heart rate with a high dose of isoproterenol (0.4 μg/kg/min) were similar in adult TG and WT rabbits. In isolated myocytes from the LV of adult rabbits, baseline percent contraction was increased, P < 0.05, in TG (11.2 ± 0.5%) compared to WT (9.3 ± 0.5%), while maximal responses to isoproterenol (100 nM) were similar in adult TG (16.2 ± 0.5%) and WT myocytes (15.6 ± 0.4%). Although TG mice with overexpressed cardiac Gsα develop cardiomyopathy at 8–12 months of age, even at 16 months of age, there was no evidence of cardiomyopathy either in terms of LV function or histology in TG rabbits. In addition, Giα was elevated in the LV of adult (8–10 months old) TG rabbits compared to WT, but not in juvenile (3–5 months old) TG rabbits. Although both TG mice and rabbits with overexpressed cardiac Gsα exhibited enhanced heart rate and contractility, the TG rabbit does not develop cardiomyopathy, potentially due to a compensatory increase in Giα.