title: Duality of n-3 Polyunsaturated Fatty Acids on Mcp-1 Expression in Vascular Smooth Muscle: A Potential Role of 4-Hydroxy Hexenal.
abstract: N-3 polyunsaturated fatty acids such as docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) have protective effects against atherosclerosis. Monocyte chemotactic protein (MCP)-1 is a major inflammatory mediator in the progression of atherosclerosis. However, little is known about the regulation of MCP-1 by DHA and EPA in vessels and vascular smooth muscle cells (VSMCs). In this study, we compared the effect of DHA and EPA on the expression of Mcp-1 in rat arterial strips and rat VSMCs. DHA, but not EPA, suppressed Mcp-1 expression in arterial strips. Furthermore, DHA generated 4-hydroxy hexenal (4-HHE), an end product of n-3 polyunsaturated fatty acids (PUFAs), in arterial strips as measured by liquid chromatography-tandem mass spectrometry. In addition, 4-HHE treatment suppressed Mcp-1 expression in arterial strips, suggesting 4-HHE derived from DHA may be involved in the mechanism of this phenomenon. In contrast, Mcp-1 expression was stimulated by DHA, EPA and 4-HHE through p38 kinase and the Keap1-Nuclear factor erythroid-derived 2-like 2 (Nrf2) pathway in VSMCs. In conclusion, there is a dual effect of n-3 PUFAs on the regulation of Mcp-1 expression. Further study is necessary to elucidate the pathological role of this phenomenon.
authors.affiliation: Department of Medicine, Shiga University of Medical Science, Shiga 520-2192, Japan. nagayama@belle.shiga-med.ac.jp.
authors.forename: Kohji
authors.initials: K
authors.lastname: Nagayama
authors.affiliation: Department of Medicine, Shiga University of Medical Science, Shiga 520-2192, Japan. morino@belle.shiga-med.ac.jp.
authors.forename: Katsutaro
authors.initials: K
authors.lastname: Morino
authors.affiliation: Department of Medicine, Shiga University of Medical Science, Shiga 520-2192, Japan. sekine@belle.shiga-med.ac.jp.
authors.forename: Osamu
authors.initials: O
authors.lastname: Sekine
authors.affiliation: Department of Medicine, Shiga University of Medical Science, Shiga 520-2192, Japan. f.nakagawa@jclbio.com.|Osaka Laboratory, JCL Bioassay Corporation, 5-16-26, Minamisuita, Suita-shi, Osaka 564-0043, Japan. f.nakagawa@jclbio.com.
authors.forename: Fumiyuki
authors.initials: F
authors.lastname: Nakagawa
authors.affiliation: Department of Medicine, Shiga University of Medical Science, Shiga 520-2192, Japan. atsushi.ishikado@jp.sunstar.com.|Sunstar Inc., 3-1 Asahi-machi, Takatsuki, Osaka 569-1195, Japan. atsushi.ishikado@jp.sunstar.com.|Joslin Diabetes Centre, Harvard Medical School, MA 02115, USA. atsushi.ishikado@jp.sunstar.com.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Ishikado
authors.affiliation: Department of Medicine, Shiga University of Medical Science, Shiga 520-2192, Japan. hiwasaki@belle.shiga-med.ac.jp.|Department of Pharmacology, Shiga University of Medical Science, Shiga 520-2192, Japan. hiwasaki@belle.shiga-med.ac.jp.
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Iwasaki
authors.affiliation: Department of Medicine, Shiga University of Medical Science, Shiga 520-2192, Japan. tokada@belle.shiga-med.ac.jp.
authors.forename: Takashi
authors.initials: T
authors.lastname: Okada
authors.affiliation: Department of Pharmacology, Shiga University of Medical Science, Shiga 520-2192, Japan. tawa@belle.shiga-med.ac.jp.
authors.forename: Masashi
authors.initials: M
authors.lastname: Tawa
authors.affiliation: Department of Medicine, Shiga University of Medical Science, Shiga 520-2192, Japan. dkst0310@belle.shiga-med.ac.jp.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Sato
authors.affiliation: Department of Pharmacology, Shiga University of Medical Science, Shiga 520-2192, Japan. timamura@belle.shiga-med.ac.jp.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Imamura
authors.affiliation: Department of Diabetes and Endocrine Medicine, Kagoshima University, Kagoshima 890-8580, Japan. ynishio@m3.kufm.kagoshima-u.ac.jp.
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Nishio
authors.affiliation: Department of Medicine, Shiga University of Medical Science, Shiga 520-2192, Japan. sugi@belle.shiga-med.ac.jp.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ugi
authors.affiliation: Kusatsu General Hospital, 1660, Yabase-cho, Kusatsu, Shiga 525-8585, Japan. kashiwagi@kusatsu-gh.or.jp.
authors.forename: Atsunori
authors.initials: A
authors.lastname: Kashiwagi
authors.affiliation: Department of Pharmacology, Shiga University of Medical Science, Shiga 520-2192, Japan. okamura@belle.shiga-med.ac.jp.
authors.forename: Tomio
authors.initials: T
authors.lastname: Okamura
authors.affiliation: Department of Medicine, Shiga University of Medical Science, Shiga 520-2192, Japan. maegawa@belle.shiga-med.ac.jp.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Maegawa
mesh_terms: D000447:Aldehydes / Q000378:metabolism*; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism*; D002853:Chromatography, Liquid; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D015118:Eicosapentaenoic Acid / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D034622:RNA Interference; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D053719:Tandem Mass Spectrometry; D013997:Time Factors; D014162:Transfection; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000447:Aldehydes; C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D051267:NF-E2-Related Factor 2; C495637:Nfe2l2 protein, rat; C045934:4-hydroxy-2-hexenal; D004281:Docosahexaenoic Acids; D015118:Eicosapentaenoic Acid; D048051:p38 Mitogen-Activated Protein Kinases
keywords: 4-hydroxy hexenal; docosahexaenoic acid; eicosapentaenoic acid; monocyte chemotactic protein 1