Abstract 140: IMP Modulates Cardiac MAPK Signal Transduction Controlling Cardiac Size And Function.
Neurohumoral activation strongly stimulates mitogen activated protein kinase (MAPK) pathways, which activate downstream effector pathways highly relevant to hypertrophy and heart failure. Impedes Mitogenic Signal Propagation (IMP) was recently identified as an important modulator of Ras dependent activation of Erk-MAPK signaling in non-cardiac cells. We identified IMP as differentially regulated upon load induced heart failure in a proteomics study. Thus, the aim of this study was to analyse the role of IMP in myocardial hypertrophy and heart failure. Adenoviruses for overexpression of IMP and a constitutively activated Raf mutant (Raf-BXB), were created to study the effects of IMP in vitro in isolated rat cardiac myocytes. Transgenic mice, overexpressing IMP cardiac-specifically under control of the aMHC promoter were created and analysed. In both adult and neonatal rat cardiac myocytes, IMP overexpression profoundly suppressed MEK and ERK MAPK activation under baseline conditions and following Raf-BXB-stimulation. This suggests an inhibitory effect of IMP on both adaptive hypertrophy and anti-apoptotic signaling. Three independently created BRAP-transgenic (TG) mouse lines in two different genetic backgrounds exhibited grossly enlarged hearts, compared to wildtype littermates (WT). Echocardiography confirmed dilation (left ventricular end-diastolic diameter 4.57±0.17 vs. 3,57±0.04 mm; p<0.05 BRAP vs. WT; p<0.05; TG vs WT) and significant reduction of fractional shortening (14±3% vs. 40±0.4%; BRAP TG vs. WT; p<0.001). Invasive hemodynamic measurements confirmed a phenotype consistent with a severe dilative cardiomyopathy. Kaplan-Maier analysis showed a significantly decreased survival with 50% of mice dying before the age of 24 weeks. MAPK signalling was profoundly altered before development of hypertrophy and exhibited a clear dynamic shift from p38 activation (prior to hypertrophy) and p38 inhibition (after onset of heart failure). Bax-Bcl ratio and cytochrome c release were dramatically enhanced in transgenic mice, consistent with increased apoptosis. These data indicate that IMP is central to control of cardiac size and function via inhibition of the Ras dependent ERK MAPK pathway and a dynamic shift in p38 MAPK activity.