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.
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-regulates the atrial natriuretic factor (ANF) gene, but does not affect skeletal alpha-actin or myosin light chain-2v expression. As evidenced by nuclear run-on transcription assays, both CT-1 and alpha-adrenergic stimulation lead to an increase in ANF gene transcription. Transient transfection analyses document that, in contrast to alpha-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 gpl30/LIFRbeta-dependent signaling pathways.
Wollert
K C
KC
Department of Medicine, Center for Molecular Genetics, University of California, San Diego, School of Medicine, La Jolla, California 92093, USA.
Taga
T
T
Saito
M
M
Narazaki
M
M
Kishimoto
T
T
Glembotski
C C
CC
Vernallis
A B
AB
Heath
J K
JK
Pennica
D
D
Wood
W I
WI
Chien
K R
KR
D000199:Actins / Q000096:biosynthesis; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000096:biosynthesis; D002478:Cells, Cultured; D020934:Ciliary Neurotrophic Factor; D016207:Cytokines / Q000096:biosynthesis / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects*; D016762:Genes, fos; D006131:Growth Inhibitors / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects*; D006801:Humans; D015850:Interleukin-6; D053605:Leukemia Inhibitory Factor; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit; D008222:Lymphokines / Q000494:pharmacology*; D051379:Mice; D009206:Myocardium / Q000166:cytology* / Q000378:metabolism / Q000473:pathology; D009414:Nerve Growth Factors / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000494:pharmacology; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis; D018121:Receptors, Cytokine / Q000502:physiology*; D053606:Receptors, OSM-LIF; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D012518:Sarcomeres / Q000187:drug effects / Q000502:physiology / Q000648:ultrastructure*; D015398:Signal Transduction; D014162:Transfection
D000199:Actins; D020934:Ciliary Neurotrophic Factor; D016207:Cytokines; D006131:Growth Inhibitors; D015850:Interleukin-6; C507837:LIF protein, human; C507840:LIFR protein, human; D053605:Leukemia Inhibitory Factor; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit; C507838:Lif protein, mouse; C507841:Lifr protein, mouse; C507842:Lifr protein, rat; D008222:Lymphokines; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D016760:Proto-Oncogene Proteins c-fos; D018121:Receptors, Cytokine; D053606:Receptors, OSM-LIF; D011993:Recombinant Fusion Proteins; D009320:Atrial Natriuretic Factor; C092073:cardiotrophin 1