NFAT: a transcriptional platform for heart failure
01 / 2008 - unknown
Heart failure is a serious clinical disorder with limited treatment options and preceded by enlargement of the cardiac muscle (cardiac hypertrophy). In fact, persistent cardiac hypertrophy is the single most important risk factor for heart failure development in humans. A hallmark feature of cardiac hypertrophy is re-activation of a fetal gene expression profile, controlled by activation of intracellular signalling cascades that regulate transcriptional events which, following biomechanical stress, evoke transcriptional activation of a fetal gene program. We therefore postulate that the hypertrophying/failing heart is subject to progressive dedifferentiation. The logical inference of this view implies that antagonizing measures for cardiac dedifferentiation may improve heart failure prognosis in the future. Over the last several years, calcineurin/NFAT signaling has been the focus of intense research interest based on the discovery that it plays a central role in the principal hypertrophic signaling cascade.1 Elevated intracellular calcium (Ca2+) levels result in the activation of the Ca2+/calmodulin-dependent phosphatase calcineurin. In turn, calcineurin dephosphorylates its transcriptional effector Nuclear Factor of Activated T-cells (NFAT), which resides inactively in the cytoplasm of unstimulated cardiomyocytes.2, 3 Upon stimulation by calcineurin, dephosphorylated NFAT is imported into the nucleus and regulates gene transcription.3 Studies by my group have clearly demonstrated that the pro-hypertrophic properties of calcineurin are contingent upon NFAT activation, leading us to believe that calcineurin-NFAT activation represents a nodal point in the control of cardiac remodeling and failure.4, 5The applicant has a demonstrable track-record in analyzing cardiac signal transduction and transcription factor biology using an integration of molecular biological techniques, gene targeting of the murine genome, and (patho)physiological phenotyping of the heart.