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Inhibition of TGFbeta signaling potentiates the FGF-2-induced stimulation of cardiomyocyte DNA synthesis.

Authors: Sheikh, F  Hirst, CJ  Jin, Y  Bock, ME  Fandrich, RR  Nickel, BE  Doble, BW  Kardami, E  Cattini, PA 
Citation: Sheikh F, etal., Cardiovasc Res. 2004 Dec 1;64(3):516-25.
Pubmed: (View Article at PubMed) PMID:15537505
DOI: Full-text: DOI:10.1016/j.cardiores.2004.08.009

OBJECTIVE: Added transforming growth factor beta (TGFbeta) inhibits the proliferation of immature cardiomyocytes. We have now examined the hypothesis that suppression of endogenous TGFbeta 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 TGFbeta type II receptor (TGFbetaRIIDeltaKD) 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 TGFbeta-TGFbetaRII suppressed endogenous FGFR-1-mediated signals that stimulate or are permissive for DNA synthesis. TGFbeta 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 TGFbeta inhibition, elicited a 3- or a 13-fold stimulation of DNA synthesis, respectively, pointing to a synergistic effect. CONCLUSION: Inhibition of TGFbetaRII-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 TGFbeta-triggered signal transduction may be required for maximal stimulation of immature cardiomyocyte DNA synthesis.


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CRRD Object Information
CRRD ID: 1601597
Created: 2007-04-25
Species: All species
Last Modified: 2007-04-25
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.