Résumé :
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Cardiac disease is a prominent feature of Emery-Dreifuss muscular dystrophy (EDMD), with the initial presentation being atrioventricular conduction block followed by dilated cardiomyopathy. Autosomal dominant EDMD and related cardiomyopathies are caused by mutations in LMNA encoding A-type nuclear lamins. EDMD is also inherited in a X-linked manner due to mutations in EMD, which encodes the inner nuclear membrane protein emerin. We studied mouse models of autosomal and X-linked EDMD to decipher pathogenic mechanisms involved in cardiomyopathy and to identify targets for therapeutic intervention. Using Affymetrix GeneChips and RNA isolated from ventricles of Lmna H222P “knock in” mice, we discovered that the JNK and ERK branches of the MAP kinase cascade are activated. Activation occurs prior to the appearance of cardiac disease, suggesting that it is a primary pathogenic mechanism. Along with activation of JNK and ERK, there is increased expression of “downstream” transcription factors, such as c-Jun, and genes they activate encoding sarcomeric proteins such as myosins and sacrolipin. In emerin-deficient mice, there is also activation of ERK and increased expression of “downstream” transcription factors and genes encoding muscle components. We have further demonstrated that expression of lamin A variants encoded by LMNA mutants causing EDMD and “knockdown” of A-type lamins and emerin using siRNA activate ERK and JNK kinases in cultured cells. These results have lead to a trial of MAP kinase inhibitors in Lmna H222P homozygous that develop dilated cardiomyopathy. Their effects on cardiac function and the expression of genes involved in the development of cardiomyopathy are currently being analyzed and will be presented.
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