Abstract 359: Inhibition of ERK-MAPK signalling via BRCA1 associated Protein 2 (BRAP) leads to Heart Failure in Transgenic Mice
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. BRCA1 Associated Protein 2 (BRAP) was recently identified as an important modulator of Ras dependent activation of ERK MAPK signaling in non-cardiac cells. We identified BRAP to be differentially regulated upon load induced heart failure in a proteomics study. Thus, the aim of this study was to analyse the role of BRAP in myocardial hypertrophy and heart failure. Adenoviruses for overexpression of BRAP and a constitutively activated Raf mutant (Raf-BXB), were created to study the effects of BRAP in vitro in isolated rat cardiac myocytes. Transgenic mice, overexpressing BRAP cardiac-specifically under control of the alpha myosin heavy chain promoter were created and analysed. In both adult and neonatal rat cardiac myocytes, BRAP overexpression profoundly suppressed both MEK and ERK MAPK activation under baseline conditions and following Raf-BXB-stimulation. This suggests an inhibitory effect of BRAP 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 severe dilative cardiomyopathy. Kaplan-Maier analysis showed a significantly decreased survival with 50% of mice dying before the age of 24 weeks. These data indicate that BRAP can profoundly control cardiac size and function via inhibition of the Ras dependent ERK MAPK pathway.