© 2004 by European Society of Cardiology
Copyright © 2004, European Society of Cardiology
Inhibition of TGFβ signaling potentiates the FGF-2-induced stimulation of cardiomyocyte DNA synthesis
aDepartment of Physiology, University of Manitoba, 730 William Avenue, Winnipeg, Manitoba, Canada R3E 3J7
bInstitute of Cardiovascular Sciences, St. Boniface Hospital Research Centre, 351 Tache Avenue, Winnipeg, Manitoba, Canada R2H 2A6
cDepartment of Human Anatomy and Cell Science, University of Manitoba, 730 William Avenue, Winnipeg, Manitoba, Canada R3E 3J7
* Corresponding author. Tel.: +1 204 789 3696; fax: +1 204 789 3934. Email address: peter_cattini{at}umanitoba.ca
Objective:: Added transforming growth factor beta (TGFβ) inhibits the proliferation of immature cardiomyocytes. We have now examined the hypothesis that suppression of endogenous TGFβ signaling will boost the proliferative response (DNA synthesis) of cardiac myocytes to serum and/or to the mitogenic factor fibroblast growth factor-2 (FGF-2).
Methods and results:: Overexpression of a kinase-deficient TGFβ type II receptor (TGFβRII
KD) resulted in a 2.8-fold increase in cardiomyocyte DNA synthesis in serum-rich cultures, an effect requiring active FGFR-1 since it was not observed in the presence of excess kinase-deficient FGFR-1. This finding suggested that endogenous TGFβ–TGFβRII suppressed endogenous FGFR-1-mediated signals that stimulate or are permissive for DNA synthesis. TGFβ had no effect, however, on the FGF-2-induced acute stimulation of extracellular signal regulated kinase1/2. FGF-2, added in the absence or presence of TGFβ inhibition, elicited a 3- or a 13-fold stimulation of DNA synthesis, respectively, pointing to a synergistic effect.
Conclusion:: Inhibition of TGFβRII-transduced signaling upregulates the proliferative response of cardiomyocytes to serum, and greatly potentiates the stimulatory effect of FGF-2. A combinatorial strategy including activation of FGF-2 and inhibition of TGFβ-triggered signal transduction may be required for maximal stimulation of immature cardiomyocyte DNA synthesis.
KEYWORDS Cardiomyocytes; DNA synthesis; Receptor crosstalk; Fibroblast growth factor-2; Transforming growth factor β; Dominant negative receptors
1 Current address: Institute of Molecular Medicine, School of Medicine, University of California-San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.