FGF-16 is released from neonatal cardiac myocytes and alters growth-related signaling: a possible role in postnatal development.
FGF-16 has been reported to be preferentially expressed in the adult rat heart. We have investigated the expression of FGF-16 in the perinatal and postnatal heart and its functional significance in neonatal rat cardiac myocytes. FGF-16 mRNA accumulation was observed by quantitative RT-PCR between neonatal days 1 and 7, with this increased expression persisting into adulthood. FGF-2 has been shown to increase neonatal rat cardiac myocyte proliferative potential via PKC activation. Gene array analysis revealed that FGF-16 inhibited the upregulation by FGF-2 of cell cycle promoting genes including cyclin F and Ki67. Furthermore, the CDK4/6 inhibitor gene Arf/INK4A was upregulated with the combination of FGF-16 and FGF-2 but not with either factor on its own. The effect on Ki67 was validated by protein immunodetection, which also showed that FGF-16 significantly decreased FGF-2-induced Ki67 labeling of cardiac myocytes, although it alone had no effect on Ki67 labeling. Inhibition of p38 MAPK potentiated cardiac myocyte proliferation induced by FGF-2 but did not alter the inhibitory action of FGF-16. Receptor binding assay showed that FGF-16 can compete with FGF-2 for binding sites including FGF receptor 1. FGF-16 had no effect on activated p38, ERK1/2, or JNK/SAPK after FGF-2 treatment. However, FGF-16 inhibited PKC-alpha and PKC-epsilon activation induced by FGF-2 and, importantly, IGF-1. Collectively, these data suggest that expression and release of FGF-16 in the neonatal myocardium interfere with cardiac myocyte proliferative potential by altering the local signaling environment via modulation of PKC activation and cell cycle-related gene expression.
Lu
Shun Yan
SY
Department of Physiology, University of Manitoba, Winnipeg, Manitoba, Canada R3E 3J7.
Sontag
David P
DP
Detillieux
Karen A
KA
Cattini
Peter A
PA
D000375:Aging / Q000502:physiology; D000818:Animals; D000831:Animals, Newborn; D018929:Cell Culture Techniques; D002453:Cell Cycle / Q000502:physiology; D002455:Cell Division; D004789:Enzyme Activation; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism*; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000235:genetics; D007700:Kinetics; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000502:physiology*; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction
C110776:Fgf16 protein, rat; D005346:Fibroblast Growth Factors; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D011493:Protein Kinase C