TY - JOUR
T1 - Cardioprotection induced by cardiac-specific overexpression of fibroblast growth factor-2 is mediated by the MAPK cascade
AU - House, Stacey L.
AU - Branch, Kevin
AU - Newman, Gilbert
AU - Doetschman, Thomas
AU - Schultz, Jo El J.
PY - 2005/11
Y1 - 2005/11
N2 - 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.
AB - 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.
KW - Extracellular signal-regulated kinase
KW - Ischemia-reperfusion injury
KW - Mitogen-activated protein kinase
KW - Myocardial infarction
KW - Signaling cross talk
KW - p38
UR - http://www.scopus.com/inward/record.url?scp=27144502042&partnerID=8YFLogxK
U2 - 10.1152/ajpheart.00392.2005
DO - 10.1152/ajpheart.00392.2005
M3 - Article
C2 - 16040717
AN - SCOPUS:27144502042
VL - 289
SP - H2167-H2175
JO - American Journal of Physiology - Heart and Circulatory Physiology
JF - American Journal of Physiology - Heart and Circulatory Physiology
SN - 0363-6135
IS - 5 58-5
ER -