title: Suppression of EC-SOD by oxLDL During Vascular Smooth Muscle Cell Proliferation.
abstract: Reactive oxygen species (ROS) produced by endothelial cells and macrophages play important roles in atherogenesis because they promote the formation of oxidized low-density lipoproteins (oxLDL). Extracellular-superoxide dismutase (EC-SOD) is mainly produced by vascular smooth muscle cells (VSMCs), is secreted into the extracellular space, and protects cells from the damaging effects of the superoxide anion. Thus, the expression of EC-SOD in VSMCs is crucial for protecting cells against atherogenesis; however, oxLDL-induced changes in the expression of EC-SOD in VSMCs have not yet been examined. We herein showed that oxLDL decreased EC-SOD mRNA and protein levels by binding to lectin-like oxidized LDL receptor-1 (LOX-1). Moreover, we demonstrated the significant role of mitogen-activated protein kinase (MEK)/extracellular-regulated protein kinase (ERK) signaling in oxLDL-elicited reductions in the expression of EC-SOD and proliferation of VSMCs. The results obtained with the FCS treatment indicate that oxLDL-elicited reductions in the expression of EC-SOD are related to the proliferation of VSMCs. We herein showed for the first time that luteolin, a natural product, restored oxLDL-induced decreases in the expression of EC-SOD and proliferation of VSMCs. Collectively, the results of the present study suggest that oxLDL accelerates the development of atherosclerosis by suppressing the expression of EC-SOD and also that luteolin has potential as a treatment for atherosclerosis. J. Cell. Biochem. 117: 2496-2505, 2016. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Department of Biomedical Pharmaceutics, Laboratory of Clinical Pharmaceutics, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu 501-1196, Japan.
authors.forename: Junya
authors.initials: J
authors.lastname: Makino
authors.affiliation: Department of Biomedical Pharmaceutics, Laboratory of Clinical Pharmaceutics, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu 501-1196, Japan.
authors.forename: Rei
authors.initials: R
authors.lastname: Asai
authors.affiliation: Department of Biomedical Pharmaceutics, Laboratory of Clinical Pharmaceutics, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu 501-1196, Japan.
authors.forename: Mao
authors.initials: M
authors.lastname: Hashimoto
authors.affiliation: Department of Biomedical Pharmaceutics, Laboratory of Clinical Pharmaceutics, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu 501-1196, Japan. tekamiya@gifu-pu.ac.jp.
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Kamiya
authors.affiliation: Department of Biomedical Pharmaceutics, Laboratory of Clinical Pharmaceutics, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu 501-1196, Japan.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Hara
authors.affiliation: Department of Chemistry and Biomolecular Science, Faculty of Engineering, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Ninomiya
authors.affiliation: Department of Chemistry and Biomolecular Science, Faculty of Engineering, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan.
authors.forename: Mamoru
authors.initials: M
authors.lastname: Koketsu
authors.affiliation: Department of Biomedical Pharmaceutics, Laboratory of Clinical Pharmaceutics, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu 501-1196, Japan.
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Adachi
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D006801:Humans; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051127:Scavenger Receptors, Class E / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013482:Superoxide Dismutase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D008077:Lipoproteins, LDL; C495137:OLR1 protein, human; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D051127:Scavenger Receptors, Class E; C099252:oxidized low density lipoprotein; C441642:SOD3 protein, human; D013482:Superoxide Dismutase
keywords: CELL GROWTH; EXTRACELLULAR-SUPEROXIDE DISMUTASE; LECTIN-LIKE OXIDIZED LDL RECEPTOR-1; MITOGEN-ACTIVATED PROTEIN KINASE; OXIDIZED LOW-DENSITY LIPOPROTEIN