Abstract 3432: Impedes Mitogenic Signal Propagation (IMP) is Essential for Embryonic Development and Controls Cardiac Size and Function via MAPK
Neurohumoral activation strongly stimulates mitogen activated protein kinase (MAPK) pathways in the heart, which signal to and activate downstream effector pathways highly relevant to hypertrophy and heart failure. IMP was recently identified as an important modulator of Ras dependent activation of MEK/ERK MAPK signaling in non-cardiac cells. We examined IMP in both adult and neonatal rat cardiac myocytes, where adenoviral IMP overexpression profoundly suppressed MEK and ERK MAPK activation under baseline conditions and following Raf-stimulation. A mammalian two-hybrid construct confirmed a direct inhibitory effect on cRaf-MEK protein-protein interaction, suggesting an inhibitory effect of IMP on both adaptive hypertrophy and anti-apoptotic signaling. Three independently created IMP-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 IMP vs. WT; p<0.05; TG vs WT) and significant reduction of fractional shortening (14±3% vs. 40±0.4%; IMP 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. Higher p38 MAPK activity, Bax/Bcl ratio and cytoplasmic cytochrome c release indicated proapoptotic signalling contributed to the phenotype. Gene-targeted IMP mice were not born in mendelian ratios, as homozygous IMP gene-targeted mice were observed to die at embryonic day 9.5–10.5, while heterozygous mice survived without phenotypic abnormalities until 12 months. These data indicate that IMP can control cardiac size and function via profoundly altered MAPK signalling and that IMP is essential to embryonic development.