Involvement of FrzA/sFRP-1 and the Wnt/frizzled pathway in ischemic preconditioning
Involvement of FrzA/sFRP-1 and the Wnt/frizzled pathway in ischemic preconditioning
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DOI：
10.1161/01.res.0000171895.06914.2c
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发表时间：
2005-06-24
影响因子：
20.1
通讯作者：
Duplàa, C
中科院分区：
文献类型：
--
作者：
Barandon, L;Dufourcq, P;Duplàa, C
缺血预适应 (PC) 过程中糖原合酶激酶 (GSK)-3 beta 通过 Akt/PI3-激酶途径磷酸化和随后失活已被证明具有心脏保护作用。由于 FrzA/sFRP-1（一种 Wnt/Frizzled 通路的分泌性拮抗剂）在心脏中表达，并且能够在体外降低血管细胞上 GSK-3 β 的磷酸化，因此我们使用在条件转基因表达方法（tet-off 系统）下在心肌细胞中过表达 FrzA（α-MHC 启动子）的转基因小鼠在 PC 期间检查了其效果。与同窝小鼠相比，PC 后转基因小鼠中 FrzA 的过度表达抑制了 GSK-3 β 磷酸化以及蛋白激酶 C (PKC) ε 激活的增加。与同窝小鼠相比，PC后转基因小鼠的磷酸化Akt (P-Akt)、磷酸化JNK或细胞质β-连环蛋白水平没有改变，磷酸化p38 (P-p38)略有增加。与同窝小鼠相比，FrzA 转基因小鼠表现出更大的梗塞面积和更严重的心功能恶化。所有这些差异都通过添加强力霉素而逆转。这项研究首次证明，破坏 β-连环蛋白独立的 Wnt/Frizzled 通路会诱导 GSK-3 β 的激活，并逆转预处理的益处。
Phosphorylation and subsequent inactivation of glycogen synthase kinase (GSK)-3 beta via the Akt/PI3-Kinase pathway during ischemic preconditioning (PC) has been shown to be cardioprotective. As FrzA/sFRP-1, a secreted antagonist of the Wnt/Frizzled pathway, is expressed in the heart and is able to decrease the phosphorylation of GSK-3 beta in vitro on vascular cells, we examined its effect during PC using transgenic mouse overexpressing FrzA in cardiomyocytes (alpha-MHC promoter) under a conditional transgene expression approach (tet-off system). Overexpression of FrzA inhibited the increase in GSK-3 beta phosphorylation as well as protein kinase C (PKC) epsilon activation in transgenic mice after PC as compared with littermates. Phospho-Akt (P-Akt), phospho-JNK, or the cytoplasmic beta-catenin levels were not modified, phospho-p38 (P-p38) was slightly increased in transgenic mice after PC as compared with littermates. FrzA transgenic mice displayed a larger infarct size and a greater worsening of cardiac function compared with littermates. All these differences were reversed by the addition of doxycycline. This study demonstrates for the first time that disruption of a beta-catenin independent Wnt/Frizzled pathway induces the activation of GSK-3 beta and reverses the benefit of preconditioning.