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Cardiovascular Research 2003 60(2):365-375; doi:10.1016/S0008-6363(03)00534-0
© 2003 by European Society of Cardiology
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Copyright © 2003, European Society of Cardiology

Induction of protein synthesis in cardiac fibroblasts by cardiotrophin-1: integration of multiple signaling pathways

Darren H Freed, Anna M Borowiec, Tatjana Angelovska and Ian M.C Dixon*

Institute of Cardiovascular Sciences, St. Boniface General Hospital Research Centre, Faculty of Medicine, University of Manitoba, 351 Tache Ave, Winnipeg, Manitoba, Canada R2H 2A6

*Corresponding author. Tel.: +1-204-235-3171; fax: +1-204-233-6723. Email address: idixon{at}sbrc.ca

Objective: Cardiotrophin-1 (CT-1) is a member of the IL-6 family of cytokines and is expressed in various cardiovascular disease states. CT-1 induces cardiomyocyte hypertrophy, and protects myocytes from ischemia reperfusion injury. We sought to elucidate CT-1 signaling in cardiac fibroblasts with respect to initiation of protein synthesis. Methods: Cardiac fibroblasts were isolated from the ventricles of 200-g Sprague–Dawley rats and stimulated with CT-1 at specified concentrations with or without inhibitors of cell signaling pathways. Activation of intracellular signaling pathways was determined by Western analysis and immunocytochemistry. Protein synthesis was measured by incorporation of [3H]leucine. Results: CT-1 treatment resulted in activation of the Jak/STAT, MAPK, and Akt pathways in addition to protein synthesis regulatory proteins with resultant increase in overall protein synthesis. Analysis with phospho-specific antibodies revealed that AG490 (Jak inhibitor), PD98059 (MEK1/2 inhibitor), SB203580 (p38 MAPK inhibitor), LY294002 (PI3-K inhibitor) and rapamycin (mTOR inhibitor) act at different levels in the signaling cascade to inhibit CT-1 induced protein synthesis. Conclusion: Cardiotrophin-1 activates the Jak/STAT, PI3K/Akt, p38 and p42/44 MAPK pathways in cardiac fibroblasts. Use of pharmacologic inhibitors reveals that each of these pathways play a role in CT-1 induced protein synthesis.

KEYWORDS Cardiotrophin; Cardiac fibroblast; Signal transduction

Time for primary review 33 days


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