title: Glycoxydation promotes vascular damage via MAPK-ERK/JNK pathways.
abstract: Oxidation and glycation enhance foam cell formation via MAPK/JNK in euglycemic and diabetic subjects. Here, we investigated the effects of glycated and oxidized LDL (glc-oxLDL) on MAPK-ERK and JNK signaling pathways using human coronary smooth muscle cells. Glc-oxLDL induced a broad cascade of MAPK/JNK-dependent signaling transduction pathways and the AP-1 complex. In glc-oxLDL treated coronary arterioles, tumor necrosis factor (TNF) α increased JNK phosphorylation, whereas protein kinase inhibitor dimethylaminopurine (DMAP) prevented the TNF-induced increase in JNK phosphorylation. The role of MKK4 and JNK were then investigated in vivo, using apolipoprotein E knockout (ApoE(-/-)) mice. Peritoneal macrophages, isolated from spontaneously hyperlipidemic but euglycemic mice showed increases in both proteins and phosphorylated proteins. Compared to streptozotocin-treated diabetic C57BL6 and nondiabetic C57BL6 Wt mice, in streptozotocin-diabetic ApoE(-/-) mice, the increment of foam cell formation corresponded to an increment of phosphorylation of JNK1, JNK2, and MMK4. Thus, we provide a first line of evidence that MAPK-ERK/JNK pathways are involved in vascular damage induced by glycoxidation.
authors.affiliation: Department of General Pathology, U.O.C. Immunohematology, and Excellence Research Centre on Cardiovascular Disease, 1st School of Medicine, Second University of Naples, Naples, Italy.
authors.forename: Filomena
authors.initials: F
authors.lastname: de Nigris
authors.forename: Monica
authors.initials: M
authors.lastname: Rienzo
authors.forename: Marcella
authors.initials: M
authors.lastname: Sessa
authors.forename: Teresa
authors.initials: T
authors.lastname: Infante
authors.forename: Elena
authors.initials: E
authors.lastname: Cesario
authors.forename: Louis J
authors.initials: LJ
authors.lastname: Ignarro
authors.forename: Mohammed
authors.initials: M
authors.lastname: Al-Omran
authors.forename: Antonio
authors.initials: A
authors.lastname: Giordano
authors.forename: Wulf
authors.initials: W
authors.lastname: Palinski
authors.forename: Claudio
authors.initials: C
authors.lastname: Napoli
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000166:cytology / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental; D005487:Foam Cells / Q000166:cytology / Q000378:metabolism; D017127:Glycation End Products, Advanced; D006801:Humans; D008077:Lipoproteins, LDL / Q000378:metabolism* / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000235:genetics; D017737:Macrophages, Peritoneal / Q000378:metabolism; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000187:drug effects / Q000235:genetics; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D010084:Oxidation-Reduction; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000093844:Glycated Proteins
chemical_list: D001057:Apolipoproteins E; D017127:Glycation End Products, Advanced; D008077:Lipoproteins, LDL; D020929:Mitogen-Activated Protein Kinase Kinases; D047428:Protein Kinase Inhibitors; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; C031797:glycated lipoproteins, LDL; D000093844:Glycated Proteins; C099252:oxidized low density lipoprotein