Interference of antihypertrophic molecules and signaling pathways with the Ca2+–calcineurin–NFAT cascade in cardiac myocytes

摘要: Cardiac hypertrophy occurs in a number of disease states associated with chronic increases cardiac work load. Although may initially represent an adaptive response the myocardium, ultimately, it often progresses to ventricular dilatation and heart failure. Much investigation has focused on signaling pathways controlling at level single myocyte. One prohypertrophic pathway that received much attention involves ubiquitously expressed Ca2+/calmodulin-activated phosphatase calcineurin. Upon activation by Ca2+, calcineurin dephosphorylates nuclear factor activated T cell (NFAT) transcription factors, leading their translocation. As common complex biological systems, is controlled simultaneously stimulatory (prohypertrophic) counter-regulatory (antihypertrophic) pathways. Given potent effects Ca2+-calcineurin-NFAT myocytes, not surprising activity this tightly multiple levels. Inhibitory mechanisms upstream (nitric oxide (NO), cGMP, cGMP-dependent protein kinase type I (PKG I), heme oxygenase-1 (HO-1), biliverdin, carbon monoxide (CO)) downstream from (glycogen synthase kinase-3 (GSK3), c-Jun N-terminal kinases (JNKs), p38 mitogen-activated (MAPKs)) have been described. Moreover, several inhibitors directly target enzymatic (cyclosporine A (CsA), tacrolimus (FK506), calcineurin-binding protein-1 (Cabin-1)/calcineurin-inhibitory (Cain), A-kinase-anchoring protein-79 (AKAP79), B homology (CHP), MCIPs, VIVIT). Considering dominant role failure, calcineurin-inhibitory strategies lead identification novel therapeutic approaches for patients disease.