Cardioprotection induced by cardiac-specific overexpression of fibroblast growth factor-2 is mediated by the MAPK cascade.
Our laboratory showed previously that cardiac-specific overexpression of FGF-2 [FGF-2 transgenic (Tg)] results in increased recovery of contractile function and decreased infarct size after ischemia-reperfusion injury. MAPK signaling is downstream of FGF-2 and has been implicated in other models of cardioprotection. Treatment of FGF-2 Tg and wild-type hearts with U-0126, a MEK-ERK pathway inhibitor, significantly reduced recovery of contractile function after global low-flow ischemia-reperfusion injury in FGF-2 Tg (86 +/- 2% vehicle vs. 66 +/- 4% U-0126; P < 0.05) but not wild-type (61 +/- 7% vehicle vs. 67 +/- 7% U-0126) hearts. Similarly, MEK-ERK inhibition significantly increased myocardial infarct size in FGF-2 Tg (12 +/- 3% vehicle vs. 31 +/- 2% U-0126; P < 0.05) but not wild-type (30 +/- 4% vehicle vs. 36 +/- 7% U-0126) hearts. In contrast, treatment of FGF-2 Tg and wild-type hearts with SB-203580, a p38 inhibitor, did not abrogate FGF-2-induced cardioprotection from postischemic contractile dysfunction. Instead, inhibition of p38 resulted in decreased infarct size in wild-type hearts (30 +/- 4% vehicle vs. 11 +/- 2% SB-203580; P < 0.05) but did not alter infarct size in FGF-2 Tg hearts (12 +/- 3% vehicle vs. 14 +/- 1% SB-203580). Western blot analysis of ERK and p38 activation revealed signaling alterations in FGF-2 Tg and wild-type hearts during early ischemia or reperfusion injury. In addition, MEK-independent ERK inhibition by p38 was observed during early ischemic injury. Together these data suggest that activation of ERK and inhibition of p38 by FGF-2 is cardioprotective during ischemia-reperfusion injury.
House
Stacey L
SL
Dept. of Pharmacology and Cell Biophysics, Univ. of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267, USA.
Branch
Kevin
K
Newman
Gilbert
G
Doetschman
Thomas
T
Schultz
Jo El J
Jel J
D000818:Animals; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000096:biosynthesis / Q000502:physiology*; D006360:Heat-Shock Proteins / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D009200:Myocardial Contraction / Q000502:physiology; D009203:Myocardial Infarction / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000235:genetics* / Q000503:physiopathology*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology
D006360:Heat-Shock Proteins; D016222:Fibroblast Growth Factor 2; D020928:Mitogen-Activated Protein Kinases