Involvement of FrzA/sFRP-1 and the Wnt/frizzled pathway in ischemic preconditioning.
Phosphorylation and subsequent inactivation of glycogen synthase kinase (GSK)-3beta 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-3beta 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-3beta 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-3beta and reverses the benefit of preconditioning.[1]References
- Involvement of FrzA/sFRP-1 and the Wnt/frizzled pathway in ischemic preconditioning. Barandon, L., Dufourcq, P., Costet, P., Moreau, C., Allières, C., Daret, D., Dos Santos, P., Daniel Lamazière, J.M., Couffinhal, T., Duplàa, C. Circ. Res. (2005) [Pubmed]
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