Cardiotrophin-1 Activates a Distinct Form of Cardiac Muscle Cell Hypertrophy ASSEMBLY OF SARCOMERIC UNITS IN SERIES VIA gp130/LEUKEMIA INHIBITORY FACTOR RECEPTOR-DEPENDENT PATHWAYS

摘要: Cardiotrophin-1 (CT-1) was recently isolated by expression cloning based on its ability to induce an increase in cell size neonatal rat ventricular cardiomyocytes. Sequence similarity data suggested that CT-1 is a novel member of family structurally related cytokines sharing the receptor component gp130. The present study documents gp130 required for signaling cardiomyocytes, demonstrating monoclonal anti-gp130 antibody completely inhibits c-fos induction CT-1. Similarly, leukemia inhibitory factor subunit beta (LIFRbeta) antagonist effectively blocks c-fos, indicating requirement LIFRbeta hypertrophic response, as well. Upon stimulation with CT-1, both gpl30 and are tyrosine-phosphorylated, providing further evidence signals through gp130/LIFRbeta heterodimer induces response cardiomyocytes distinct from phenotype seen after alpha-adrenergic stimulation, regard morphology gene pattern. Stimulation results cardiac characterized length but no significant change width. Confocal laser microscopy stimulated cells reveals assembly sarcomeric units series rather than parallel, stimulation. pattern immediate early genes, up-regulates atrial natriuretic (ANF) gene, does not affect skeletal alpha-actin or myosin light chain-2v expression. As evidenced nuclear run-on transcription assays, lead ANF transcription. Transient transfection analyses document that, contrast responsive cis-regulatory elements located outside proximal 3 kilobase pairs 5'-flanking region. These studies indicate can activate form myocardial hypertrophy, promotion sarcomere series, via gpl30/LIFRbeta-dependent pathways.