Published online before print May 26, 2005, doi: 10.1161/01.RES.0000171895.06914.2c
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Submitted on December 16, 2003
Revised on May 12, 2005
Accepted on May 18, 2005
Involvement of FrzA/sFRP-1 and the Wnt/Frizzled Pathway in Ischemic Preconditioning
Laurent Barandon ;
From the Departments of Cardiovascular Surgery (L.B.) and Cardiology (P.D.S., T.C.), Hôpital Haut Lévêque, Pessac, France; Inserm U441 (L.B., P.D., C.M., C.A., D.D., P.D.S., J.-M.D.L., T.C., C.D.) and the Center for Transgene Technology (P.C.), Université de Bordeaux 2, Pessac, France.
* To whom correspondence should be addressed. E-mail: thierry.couffinhal{at}bordeaux.inserm.fr.
Phosphorylation and subsequent inactivation of glycogen synthase kinase (GSK)-3
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 in vitro on vascular cells, we examined its effect during PC using transgenic mouse overexpressing FrzA in cardiomyocytes (
-MHC promoter) under a conditional transgene expression approach (tet-off system). Overexpression of FrzA inhibited the increase in GSK-3 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 -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 -catenin independent Wnt/Frizzled pathway induces the activation of GSK-3 and reverses the benefit of preconditioning.
Key words: animal models of human disease • cell signaling/signal transduction • genetically-altered mice • ischemia • heart
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