The cardioprotective effect of the low molecular weight isoform of fibroblast growth factor-2: the role of JNK signaling.
Our laboratory showed that overexpression of fibroblast growth factor-2 (FGF2) protected the heart against ischemia-reperfusion injury. FGF2 has different protein isoforms (low [LMW] and high [HMW] molecular weight isoforms) produced from alternative translation start sites. However, which FGF2 isoform(s) mediates this cardioprotection, and which signaling pathway (i.e., mitogen-activated protein kinase (MAPK)) elicits FGF2 isoform-induced cardioprotection remains to be elucidated.


RESULTS
Wildtype, Fgf2 KO (absence of all FGF2 isoforms) and FGF2 LMWKO (absence of LMW isoform) hearts were subjected to an ex vivo work-performing heart ischemic model of 60 min ischemia and 120 min reperfusion. There was a significant decrease in the recovery of post-ischemic contractile function (p<0.05) in Fgf2 KO and FGF2 LMWKO mouse hearts compared to wildtype hearts. Following ischemia-reperfusion injury, MKK4/7, JNK, and c-Jun were significantly phosphorylated (i.e., activated), and the levels of TUNEL-positive nuclei and caspase 3 cleavage were significantly increased in vehicle-treated Fgf2 KO and FGF2 LMWKO compared to wildtype hearts (p<0.05). A novel JNK pathway inhibitor, CEP11004 (50 nM), significantly restored the post-ischemic contractile function and reduced myocardial cell death, as measured by CK release and apoptotic markers, compared to DMSO-treated cohorts (p<0.05). Overall, our data indicate that the LMW isoform has an important role in restoring cardiac function after ischemia-reperfusion (I/R) injury. These results provide unequivocal evidence that inhibition of JNK signaling is involved in FGF2 LMW isoform-mediated cardioprotection and that the potential mechanism may be through inhibition of the apoptotic process.
Liao
Siyun
S
Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, 231 Albert Sabin Way, ML 0575, Cincinnati, OH 45267, USA.
Porter
Darius
D
Scott
Alana
A
Newman
Gilbert
G
Doetschman
Thomas
T
Schultz
Jo El J
Jel J
D000818:Animals; D002316:Cardiotonic Agents / Q000378:metabolism*; D053148:Caspase 3 / Q000378:metabolism; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D066298:In Vitro Techniques; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008970:Molecular Weight; D009200:Myocardial Contraction; D009203:Myocardial Infarction / Q000378:metabolism / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000502:physiology
D002316:Cardiotonic Agents; D020033:Protein Isoforms; D016222:Fibroblast Growth Factor 2; D048031:JNK Mitogen-Activated Protein Kinases; D053148:Caspase 3