Abstract 19099: The Pro-Hypertrophic High Molecular Weight Fgf2 Activates Ampk or Erk by Engaging, Respectively, Fgfr1-Independent or Fgfr1-Dependent Pathways
Fibroblast growth factor 2 (Fgf2) is a multifunctional protein produced as >20 kDa high (Hi-) or 18 kDa low (Lo-) molecular weight isoforms in the heart. Both types of isoforms are secreted and exert similar (acute cardioprotection) and isoform-selective effects; the latter include stimulation of cardiomyocyte hypertrophy by Hi- but not Lo-Fgf2. It is not known if Fgf2 isoforms can activate the same receptors in cardiomyocytes. Since FGFR1 is a major cardiomyocyte receptor we used FGFR1 inhibitors to test the hypothesis that Fgf2 may activate Erk (a central signal in multiple pathways) or AMP-activated kinase (Ampk), a kinase regulating cardiac metabolism, regardless of FGFR1 activation, in an isoform-selective manner.
Methods/Results: Primary cultures of neonatal rat cardiomyocytes were stimulated with Hi- or Lo-Fgf2, in the absence or presence of pharmacological FGFR1 inhibitors including SU5402 and PD173074. Activation of FGFR1, AMPK, ERK, and p38 were assessed by western blotting with corresponding phospho (p)-specific antibodies. Both Hi- and Lo-Fgf2 upregulated pY766-FGFR1. Both Hi- and Lo-FGF2 upregulated pErk, and the effect was blunted by FGFR1 inhibition. Hi-, but not Lo- FGF2, upregulated pAmpk and p38, even in the presence of FGFR1 inhibitors. LDN193189, an inhibitor of the Bone Morphogenic Protein (BMP)- Activin A receptor type 1 (ALK2) pathway, prevented the Hi-Fgf2-induced Ampk/p38 activation suggesting that Hi-Fgf2 can engage BMP receptor(s). Compound C, an inhibitor of Ampk and BMP type 1 receptors, prevented the acute protective effects of Hi-FGF2 against doxorubicin-induced cardiomyocyte cell death. Hearts from mice expressing only Hi-Fgf2 had higher pAmpk content compared to mice expressing only Lo-Fgf2, in both male and female groups, validating a link between Hi-Fgf2 and Ampk activation in vivo. In conclusion, we have shown for the first time that Hi-Fgf2, but not Lo-Fgf2, can exert FGFR1-independent effects in cardiomyocytes, likely by engaging ALK2. It remains to be determined whether the reported anti-hypertrophic effect of LDN193189 reflects inhibition of Hi-Fgf2 signal transduction.
Author Disclosures: N. Koleini: None. B.E. Nickel: None. R.R. Fandrich: None. P.A. Cattini: None. E. Kardami: None.
- © 2016 by American Heart Association, Inc.