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首页> 外文期刊>American Journal of Physiology >The protein kinase C pathway mediates cardioprotection induced by cardiac-specific overexpression of fibroblast growth factor-2.
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The protein kinase C pathway mediates cardioprotection induced by cardiac-specific overexpression of fibroblast growth factor-2.

机译：蛋白激酶C通路介导由成纤维细胞生长因子2的心脏特异性过表达诱导的心脏保护作用。

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Elucidation of protective mechanisms against ischemia-reperfusion injury is vital to the advancement of therapeutics for ischemic heart disease. Our laboratory has previously shown that cardiac-specific overexpression of fibroblast growth factor-2 (FGF2) results in increased recovery of contractile function and decreased infarct size following ischemia-reperfusion injury and has established a role for the mitogen-activated protein kinase (MAPK) signaling cascade in the cardioprotective effect of FGF2. We now show an additional role for the protein kinase C (PKC) signaling cascade in the mediation of FGF2-induced cardioprotection. Overexpression of FGF2 (FGF2 Tg) in the heart resulted in decreased translocation of PKC-delta but had no effect on PKC-alpha, -epsilon, or -zeta. In addition, multiple alterations in PKC isoform translocation occur during ischemia-reperfusion injury in FGF2 Tg hearts as assessed by Western blot analysis and confocal immunofluorescent microscopy. Treatment of FGF2 Tg and nontransgenic (NTg) hearts with the PKC inhibitor bisindolylmaleimide (1 micromol/l) revealed the necessity of PKC signaling for FGF2-induced reduction of contractile dysfunction and myocardial infarct size following ischemia-reperfusion injury. Western blot analysis of FGF2 Tg and NTg hearts subjected to ischemia-reperfusion injury in the presence of a PKC pathway inhibitor (bisindolylmaleimide, 1 micromol/l), an mitogen/extracellular signal-regulated kinase/extracellular signal-regulated kinase (MEK/ERK) pathway inhibitor (U-0126, 2.5 micromol/l), or a p38 pathway inhibitor (SB-203580, 2 micromol/l) revealed a complicated signaling network between the PKC and MAPK signaling cascades that may participate in FGF2-induced cardioprotection. Together, these data suggest that FGF2-induced cardioprotection is mediated via a PKC-dependent pathway and that the PKC and MAPK signaling cascades are integrally connected downstream of FGF2.
机译：阐明针对缺血-再灌注损伤的保护机制对于缺血性心脏病的治疗方法的发展至关重要。我们的实验室先前已表明，缺血再灌注损伤后心脏特异性成纤维细胞生长因子2（FGF2）的过度表达导致收缩功能恢复增加和梗死面积减小，并且对促分裂原激活的蛋白激酶（MAPK）发挥了作用在FGF2的心脏保护作用中信号级联。我们现在显示在FGF2诱导的心脏保护介导中的蛋白激酶C（PKC）信号级联的附加作用。心脏中FGF2（FGF2 Tg）的过度表达导致PKC-δ的移位减少，但对PKC-α，-ε或-zeta没有影响。此外，通过Western印迹分析和共聚焦免疫荧光显微镜评估，FGF2 Tg心脏缺血再灌注损伤期间PKC亚型易位发生多种变化。用PKC抑制剂bisindolylmaleimide（1 micromol / l）治疗FGF2 Tg和非转基因（NTg）心脏表明，PKC信号传导对于FGF2诱导的缺血再灌注损伤后收缩功能障碍和心肌梗死面积的减少是必要的。在PKC途径抑制剂（bisindolylmaleimide，1 micromol / l），有丝分裂原/细胞外信号调节激酶/细胞外信号调节激酶（MEK / ERK）存在下，缺血再灌注损伤的FGF2 Tg和NTg心脏的蛋白质印迹分析途径抑制剂（U-0126，2.5 micromol / l）或p38途径抑制剂（SB-203580，2 micromol / l）揭示了PKC和MAPK信号级联之间可能存在复杂的信号网络，可能参与FGF2诱导的心脏保护。总之，这些数据表明，FGF2诱导的心脏保护作用是通过PKC依赖性途径介导的，并且PKC和MAPK信号级联反应是FGF2下游的整体连接。

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