Abstract 391: Inhibition of p38α MAPK Rescues Overexpressed Cardiac 32-Adrenergic Receptor but not β1- Adrenergic Receptor Induced Cardiomyopathy
We examined the extent to which inhibiting p38α MAPK affected the development of cardiomyopathy induced by either β1- or β2- adrenergic receptor (AR) cardiac overexpression, by mating mice with overexpression of either β1-AR and β2-AR with dominant negative p38α MAPK mice. Both β1-AR and β2-AR overexpressing mice demonstrated enhanced LV function (LV ejection fraction; LVEF) as young adults and both models developed cardiomyopathy at 11–15 months of age. The severity of the cardiomyopathy was similar in β1-AR- and β2-AR overexpressed mice compared to WT control mice, and characterized by reduced LVEF [50±2% (β1) and 49+3% (β2) vs. 70+1% (WT)], increased cardiac myocyte cross sectional area [380±3.4 μm2 (β1) and 311±29 μm2 (β2) vs. 193+13 μm2 (WT)], and increased myocardial collagen [6.9±103% (β1) and 5.2+0.4% (β2) vs. 0.5+.04% (WT)]. The cardio-myopathy in bigenic (β1-AR × DNp38α) mice was not ameliorated, i.e., there was no improvement in LVEF, reduction in fibrosis, apoptosis, or myocyte hypertrophy. In contrast, the cardiomyopathy in bigenic (β2-AR × DNp38α) mice was, to a large extent, rescued; LVEF was no longer depressed in older bigenics (78±2%) compared to older β2-AR overexpressors (49±3%) and both apoptosis and fibrosis were reduced, p<0.05, by roughly 50%; however, the extent of myocyte hypertrophy was not diminished. Thus, inhibition of the p38γ MAPK pathway rescued the depressed LV function and reduced apoptosis and fibrosis in β2-AR transgenic mice, but not β1-AR transgenic mice, and myocyte hypertrophy was not reduced in either model. This suggests that p38α MAPK is a critical downstream signal important for the development of cardiomyopathy following chronic β2, but not β1-AR stimulation. Interestingly, p38β MAPK is not required for myocyte hypertrophy induced by either chronic β1 or β2-AR stimulation.