Nuclear Factor of Activated T cells (NFAT): key regulator of cardiac hypertrophy and skeletal muscle adaptation

Abstract

Despite significant progress in the prevention and treatment of cardiovascular diseases, heart failure is still a leading cause of morbidity and mortality in industrial countries. Sustained cardiac hypertrophy, which is defined as an increase in heart size resulting from an increase in cardiomyocyte cell volume, has been recognized as the single most important risk factor for heart failure development. Cardiac hypertrophy can be initiated by a wide array of (neuro/humoral) growth factors in response to increased workload, injury, or intrinsic defects in contractile performance. To understand the molecular determinants of the hypertrophic response and to achieve future rational drug design to treat heart failure, investigation currently focuses on identifying and characterizing intracellular signal transduction pathways in the heart. The experiments presented in this thesis focus on a signaling pathway which plays a role in the hypertrophic transcriptional response of the myocyte. This signaling route employs the Ca2+-calmodulin-dependent phosphatase calcineurin and its immediate downstream transcriptional effector Nuclear Factor of Activated T-cells (NFAT), and further focuses on the immediate downstream NFAT target genes in cardiac muscle.