E-cadherin/beta-catenin/T-cell factor pathway is involved in smooth muscle cell proliferation elicited by oxidized low-density lipoprotein.
The E-cadherin/beta-catenin/T-cell factor (Tcf) signaling pathway plays a crucial role in embryogenesis and carcinogenesis and has recently emerged in atherosclerosis. The aim of this work was to investigate whether this signaling pathway is involved in smooth muscle cell proliferation induced by oxidized low-density lipoprotein (LDL). In human aortic smooth muscle cells, mitogenic concentration of mildly oxidized LDL induced the activation of beta-catenin, as assessed by the dissociation of the beta-catenin/cadherin complex, and the concomitant rise of active beta-catenin in the cytosol. The oxidized LDL-induced rise of active beta-catenin required metalloproteinase activation, as well as epidermal growth factor receptor and Src signaling, as assessed by the use of pharmacological inhibitors and cells overexpressing a SrcK-inactive form. The concomitant phosphatidylinositol 3-kinase/Akt activation and glycogen synthase kinase 3-beta phosphorylation induced the inhibition of the proteasomal degradation of beta-catenin. Then active beta-catenin associated with Tcf4 and translocated into the nucleus. This enhanced the expression of the cell cycle activator cyclin D1. This crucial role of beta-catenin in the mitogenic effect of oxidized LDL was confirmed by silencing beta-catenin by specific small interfering RNA that blocked DNA synthesis. Immunohistochemistry staining of stable and disrupted plaques from carotid endarterectomy sections showed a correlation between active beta-catenin and Ki67, a proliferation marker, and a more intense staining in the smooth muscle cell layer surrounding the lipid core of disrupted plaques. In conclusion, the beta-catenin pathway is required for the mitogenic effect of oxidized LDL on human aortic smooth muscle cells. This study highlights the putative important role of the E-cadherin/beta-catenin/Tcf signaling pathway in atherosclerosis.
Bedel
Aurélie
A
Institut National de la Santé et de la Recherche Médicale U858, Toulouse, France.
Nègre-Salvayre
Anne
A
Heeneman
Sylvia
S
Grazide
Marie-Hélène
MH
Thiers
Jean-Claude
JC
Salvayre
Robert
R
Maupas-Schwalm
Françoise
F
D001011:Aorta / Q000378:metabolism; D050197:Atherosclerosis / Q000378:metabolism*; D015415:Biomarkers / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism*; D002339:Carotid Arteries / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects*; D002471:Cell Transformation, Neoplastic / Q000378:metabolism; D002478:Cells, Cultured; D056741:Cyclin D; D016213:Cyclins / Q000378:metabolism; D004247:DNA / Q000096:biosynthesis; D047108:Embryonic Development / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D019394:Ki-67 Antigen / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism / Q000494:pharmacology*; D020782:Matrix Metalloproteinases / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D010770:Phosphotransferases / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D034741:RNA, Small Interfering; D015398:Signal Transduction; D051820:TCF Transcription Factors / Q000378:metabolism*; D051176:beta Catenin / Q000037:antagonists & inhibitors / Q000378:metabolism*
D015415:Biomarkers; D015820:Cadherins; D056741:Cyclin D; D016213:Cyclins; D019394:Ki-67 Antigen; D008077:Lipoproteins, LDL; D034741:RNA, Small Interfering; D051820:TCF Transcription Factors; D051176:beta Catenin; C099252:oxidized low density lipoprotein; D004247:DNA; D010770:Phosphotransferases; D020782:Matrix Metalloproteinases; D046988:Proteasome Endopeptidase Complex