High and Low Molecular Weight Fibroblast Growth Factor-2 Increase Proliferation of Neonatal Rat Cardiac Myocytes but Have Differential Effects on Binucleation and Nuclear Morphology

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Abstract
Basic fibroblast growth factor (FGF-2) plays a vital role in the growth and differentiation of cardiac myocytes. It exists in high and low molecular weight forms because of the use of alternative initiation codons in the same mRNA. Higher levels of high molecular weight forms (molecular mass of 22 and 21.5 kD) are present in the rat heart during the neonatal stage, whereas the low molecular weight form (molecular mass of 18 kD) is predominant in the adult heart, suggesting different roles in development. Rat FGF-2 cDNAs that can preferentially express high or low molecular weight forms were introduced into neonatal rat ventricular myocyte cultures. Significant and comparable increases in overall cardiac myocyte DNA synthesis and proliferation were seen with 22/21.5- and 18-kD FGF-2 expression. A significantly higher mitotic index was seen in the vicinity of cardiac myocytes overexpressing high or low molecular weight forms of FGF-2 compared with nonoverexpressing cells. This increase was inhibited in the presence of neutralizing antibodies to FGF-2, pointing to a proximity-dependent paracrine effect of 22/21.5- and 18-kD FGF-2 on mitosis. By contrast, overexpression of high but not low molecular weight FGF-2 was associated with a significant increase in binucleation (≈36% of cardiac myocytes overexpressing 22/21.5-kD FGF-2 were binucleated compared with 9% of cardiac myocytes overexpressing 18-kD FGF-2), which was not affected by neutralizing antibodies to FGF-2. These results suggest that 22/21.5-kD FGF-2 and 18-kD FGF-2 have similar paracrine effects on proliferation but that 22-21.5-kD FGF-2 exerts a distinct intracrine effect on binucleation.

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