title: Lipid peroxidation-induced VEGF expression in the skin of KKAy obese mice.
abstract: Obesity is known to be associated with a number of effects on skin physiology. KKA(y) obese mouse is a model of type 2 diabetes characterized by systemic oxidative stress because of severe obesity, hypertriglyceridaemia, hyperglycaemia and hyperinsulinaemia. We investigated lipid peroxidation and vascular endothelial growth factor (VEGF) expression in the skin of KKA(y) obese mice. We also investigated the effect of lipid peroxidation derivatives on VEGF production and proliferation in human epidermal keratinocyte cell line (HaCaT). The lipid peroxidation level in the mouse skin tissue was determined by measuring the levels of thiobarbituric acid-reactive substances. The levels of VEGF expression, p44/p42 mitogen-activated protein kinase (MAPK) activation and CD36 expression were analysed by Western blot. Their localization was examined by immunofluorescence. For the in vitro experiments, an enzyme-linked immunosorbent assay was utilized to measure VEGF secretion in the medium. In vitro experiments demonstrated that lipid peroxidation derivatives increased VEGF production in HaCaT cells, which was blocked by a p44/p42 MAPK inhibitor and anti-CD36 antibody. We observed increased levels of lipid peroxidation derivatives, p44/p42 MAPK activation and VEGF expression in the skin of KKA(y) obese mice. Notably, pitavastatin, an inhibitor of competitive 3-hydroxy-3-methylglutaryl coenzyme A reductase, suppressed all of these processes. Our results suggest that lipid peroxidation induces VEGF expression via CD36 and p44/p42 MAPK pathway in the skin of obese mice.
authors.affiliation: Department of Dermatology, Faculty of Medicine, Kagawa University, Kita-gun, Kagawa, Japan. kozo@kms.ac.jp
authors.forename: Kozo
authors.initials: K
authors.lastname: Nakai
authors.forename: Kozo
authors.initials: K
authors.lastname: Yoneda
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Ishihara
authors.forename: Koji
authors.initials: K
authors.lastname: Ohmori
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Moriue
authors.forename: Junsuke
authors.initials: J
authors.lastname: Igarashi
authors.forename: Masakazu
authors.initials: M
authors.lastname: Kohno
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Kosaka
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Kubota
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000494:pharmacology; D018955:CD36 Antigens / Q000276:immunology; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D004195:Disease Models, Animal; D004817:Epidermis / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects / Q000502:physiology*; D008077:Lipoproteins, LDL / Q000494:pharmacology; D008244:Lysophosphatidylcholines / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011804:Quinolines / Q000494:pharmacology; D012867:Skin / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: D000906:Antibodies; D018955:CD36 Antigens; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008077:Lipoproteins, LDL; D008244:Lysophosphatidylcholines; D011804:Quinolines; D017392:Thiobarbituric Acid Reactive Substances; D042461:Vascular Endothelial Growth Factor A; C099252:oxidized low density lipoprotein; C467480:vascular endothelial growth factor A, mouse; C006065:We 201; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; C108475:pitavastatin