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.
Barandon
Laurent
L
Department of Cardiovascular Surgery, Hôpital Haut Lévêque, Pessac, France.
Dufourcq
Pascale
P
Costet
Pierre
P
Moreau
Catherine
C
Allières
Cécile
C
Daret
Danièle
D
Dos Santos
Pierre
P
Daniel Lamazière
Jean-Marie
JM
Couffinhal
Thierry
T
Duplàa
Cécile
C
D000818:Animals; D003598:Cytoskeletal Proteins / Q000032:analysis; D004318:Doxycycline / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology*; D019157:Ischemic Preconditioning, Myocardial; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D009203:Myocardial Infarction / Q000628:therapy; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction / Q000502:physiology*; D015534:Trans-Activators / Q000032:analysis; D051153:Wnt Proteins; D051176:beta Catenin; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000094742:Secreted Frizzled-Related Proteins
D003598:Cytoskeletal Proteins; D004318:Doxycycline; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D015534:Trans-Activators; D051153:Wnt Proteins; D051176:beta Catenin; D048051:p38 Mitogen-Activated Protein Kinases; C495267:CTNNB1 protein, mouse; C485539:Sfrp1 protein, mouse; D000094742:Secreted Frizzled-Related Proteins; C000605507:Gsk3b protein, mouse