Cardiotrophin-1 Activates a Distinct Form of Cardiac Muscle Cell Hypertrophy

作者：Kai Christoph Wollert, Tetsuya Taga, Mikiyoshi Saito, Masashi Narazaki, Tadamitsu Kishimoto, Christopher C. Glembotski, Ann B. Vernallis, John K. Heath, Diane Pennica, William I. Wood, Kenneth R. Chien · 发表于：Journal of Biological Chemistry · 年份：1996 · DOI：10.1074/jbc.271.16.9535 · 被引用次数：374 · 研究领域：Cardiac Fibrosis and Remodeling、Viral Infections and Immunology Research、Muscle Physiology and Disorders

Cardiotrophin-1 (CT-1) was recently isolated by expression cloning based on its ability to induce an increase in cell size in neonatal rat ventricular cardiomyocytes. Sequence similarity data suggested that CT-1 is a novel member of a family of structurally related cytokines sharing the receptor component gp130. The present study documents that gp130 is required for CT-1 signaling in cardiomyocytes, by demonstrating that a monoclonal anti-gp130 antibody completely inhibits c-fos induction by CT-1. Similarly, a leukemia inhibitory factor receptor subunit beta (LIFRbeta) antagonist effectively blocks the CT-1 induction of c-fos, indicating a requirement for LIFRbeta in the hypertrophic response, as well. Upon stimulation with CT-1, both gpl30 and the LIFRbeta are tyrosine-phosphorylated, providing further evidence that CT-1 signals through the gp130/LIFRbeta heterodimer in cardiomyocytes. CT-1 induces a hypertrophic response in cardiomyocytes that is distinct from the phenotype seen after alpha-adrenergic stimulation, both with regard to cell morphology and gene expression pattern. Stimulation with CT-1 results in an increase in cardiac cell size that is characterized by an increase in cell length but no significant change in cell width. Confocal laser microscopy of CT-1 stimulated cells reveals the assembly of sarcomeric units in series rather than in parallel, as seen after alpha-adrenergic stimulation. CT-1 induces a distinct pattern of immediate early genes, and up-regulate...