Abstract 91: Pathogenicity of Naturally Produced Fragments of Cardiac Myosin Binding Protein C and Their Effects on Heart Function and Failure

Abstract

Background: Myosin binding protein C (MyBP-C) is a thick filament protein consisting of 1274 amino acid residues (149kD) and mutations in the cardiac isoform (cardiac MyBP-C; cMyBP-C) are responsible for a substantial proportion (20-35%) of identified cases of familial hypertrophic cardiomyopathy (FHC). Recently we found a 40kD fragment is produced from cMyBP-C when the heart is stressed, using a stimulus such as ischemia reperfusion injury. This fragment can be detected in both the mouse and human heart and appears to be stable. Its ability to interfere with normal cardiac function is unexplored. Methods and Results: To understand the potential pathogenicity of the 40kd fragment in vivo, we generated cardiac myocyte-specific transgenic mice (TG) using a Tet-Off inducible system to permit controlled expression in cardiomyocytes. When 40kD protein expression is induced by crossing the responder animals with tetracycline transactivator (tTA) mice, the double TG mice show protein expression and, subsequently, sarcomere dysgenesis and altered cardiac geometry. The double transgenic heart fails between 3 to 17 weeks of age. Expression, the fragment in cardiomyocytes led to development of significant cardiac hypertrophy with myofibrillar disarray and fibrosis. Subsequent analyses showed that MEK-ERK hypertrophic signaling pathways were activated. To determine the role of this pathway in the pathogenic response being generated, we subjected an experimental cohort of animals to treatment with the MAPK/ERK kinase inhibitor U0126 during pregnancy. The drug effectively improved heart function and prolonged survival as compared to the untreated control cohort. Conclusions: The data show that a 40kD fragment of cMyBP-C, which is generated during the development of heart disease in both the mouse and human, is a pathogenic fragment whose presence leads to hypertrophic cardiomyopathy and heart failure. Blockade of the MEK-ERK pathway was effective therapeutically in decreasing morbidity and increasing lifespan in the face of continued synthesis of the fragment.