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(Circulation Research. 2005;96:1299.)
© 2005 American Heart Association, Inc.

Integrative Physiology

Involvement of FrzA/sFRP-1 and the Wnt/Frizzled Pathway in Ischemic Preconditioning

Laurent Barandon, Pascale Dufourcq, Pierre Costet, Catherine Moreau, Cécile Allières, Danièle Daret, Pierre Dos Santos, Jean-Marie Daniel Lamazière, Thierry Couffinhal, Cécile Duplàa

From the Departments of Cardiovascular Surgery (L.B.) and Cardiology (P.D.S., T.C.), Hôpital Haut Lévêque, Pessac, France; and 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.

Correspondence to Dr Thierry Couffinhal, Inserm U 441, Ave du Haut-Lévêque, 33600 Pessac, France. E-mail thierry.couffinhal{at}bordeaux.inserm.fr

Phosphorylation and subsequent inactivation of glycogen synthase kinase (GSK)-3ß 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-3ß 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-3ß 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 ß-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 ß-catenin independent Wnt/Frizzled pathway induces the activation of GSK-3ß 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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