Cardioprotection induced by cardiac-specific overexpression of fibroblast growth factor-2 is mediated by the MAPK cascade
Cardioprotection induced by cardiac-specific overexpression of fibroblast growth factor-2 is mediated by the MAPK cascade
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DOI：
10.1152/ajpheart.00392.2005
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发表时间：
2005-11-01
影响因子：
4.8
通讯作者：
Schultz, JEJ
中科院分区：
文献类型：
--
作者：
House, SL;Branch, K;Schultz, JEJ
我们的实验室先前表明，心脏特异性过表达FGF-2 [FGF-2转基因（Tg）]导致缺血再灌注损伤后收缩功能恢复增加和梗死面积减少。MAPK信号传导是FGF-2的下游，并且已经涉及其他心脏保护模型。用MEK-ERK通路抑制剂U-0126处理FGF-2 Tg和野生型心脏，显著降低了FGF-2 Tg大鼠全脑低流量缺血-再灌注损伤后收缩功能的恢复。（86 +/-2%媒介物对66 +/-4%U-0126; P < 0.05），但不是野生型（61 +/-7%媒介物对67 +/-7%U-0126）心脏。类似地，MEK-ERK抑制显著增加FGF-2 Tg心脏中的心肌梗死面积（12 +/-3%媒介物对31 +/-2%U-0126; P < 0.05），但不增加野生型心脏中的心肌梗死面积（30 +/-4%媒介物对36 +/-7%U-0126）。相比之下，用SB-203580（一种p38抑制剂）治疗FGF-2 Tg和野生型心脏，并没有消除FGF-2诱导的缺血后收缩功能障碍的心脏保护作用。相反，p38的抑制导致野生型心脏中梗死面积减小（30 +/-4%媒介物对11 +/-2%SB-203580; P < 0.05），但没有改变FGF-2 Tg心脏中的梗死面积（12 +/-3%媒介物对14 +/-1%SB- 203580）。ERK和p38激活的蛋白质印迹分析揭示了在早期缺血或再灌注损伤期间FGF-2 Tg和野生型心脏中的信号改变。此外，在早期缺血性损伤期间观察到p38对MEK非依赖性ERK的抑制。总之，这些数据表明，激活ERK和抑制p38的FGF-2是心脏缺血再灌注损伤过程中的保护。
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.