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

Kai C. 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

Research output: Contribution to journalArticlepeer-review

321 Scopus citations

Abstract

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 β (LIFRβ) antagonist effectively blocks the CT-1 induction of c-fos, indicating a requirement for LIFRβ in the hypertrophic response, as well. Upon stimulation with CT-1, both gp130 and the LIFRβ are tyrosine-phosphorylated, providing further evidence that CT-1 signals through the gp130/LIFRβ heterodimer in cardiomyocytes. CT-1 induces a hypertrophic response in cardiomyocytes that is distinct from the phenotype seen after α-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 α-adrenergic stimulation. CT-1 induces a distinct pattern of immediate early genes, and up-regulates the atrial natriuretic factor (ANF) gene, but does not affect skeletal α-actin or myosin light chain-2v expression. As evidenced by nuclear run-on transcription assays, both CT-1 and α-adrenergic stimulation lead to an increase in ANF gene transcription. Transient transfection analyses document that, in contrast to α-adrenergic stimulation, the CT-1 responsive cis-regulatory elements are located outside of the proximal 3 kilobase pairs of the ANF 5′-flanking region. These studies indicate that CT-1 can activate a distinct form of myocardial cell hypertrophy, characterized by the promotion of sarcomere assembly in series, via gp13/LIFRβ-dependent signaling pathways.

Original languageEnglish (US)
Pages (from-to)9535-9545
Number of pages11
JournalJournal of Biological Chemistry
Volume271
Issue number16
DOIs
StatePublished - Apr 19 1996
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Fingerprint

Dive into the research topics of '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'. Together they form a unique fingerprint.

Cite this