title: Shikonin inhibits oxidized LDL-induced monocyte adhesion by suppressing NFκB activation via up-regulation of PI3K/Akt/Nrf2-dependent antioxidation in EA.hy926 endothelial cells.
abstract: Oxidized low-density lipoprotein (oxLDL) is a key contributor to atherogenesis through multiple mechanisms, including the reactive oxygen species (ROS)-mediated nuclear factor-kappaB (NFκB) signaling pathway. Although shikonin, one of the main active components isolated from the Chinese herb Lithospermum erythrorhizon, has been shown to possess cardioprotective, antioxidative, and anti-inflammatory effects, the mechanisms underlying these actions are not well understood. In this study, we used EA.hy926 endothelial-like cells to examine the anti-atherogenic activity of shikonin. Shikonin (0-1 μM) concentration-dependently induced heme oxygenase-1, glutamate cysteine ligase modifier subunit, catalase, superoxide dismutase 1, glutathione peroxidase 1, and glutathione reductase protein and mRNA expression and glutathione content via activation of the phosphatidylinositol 3-kinase (PI3K)/Akt/Nrf2 signaling pathway. In the presence of oxLDL (40 μg/ml), shikonin pretreatment reversed oxLDL-induced ROS production, antioxidant response element reporter activity, NFκB nuclear translocation, and intercellular adhesion molecule (ICAM)-1 and E-selectin expression and suppressed the increase of monocyte adhesion to endothelial cells. Nrf2 knockdown by using RNA interference attenuated the ability of shikonin to inhibit oxLDL-induced NFκB DNA binding activity, adhesion molecule expression, and monocyte adhesion. Taken together, these results suggest that shikonin protects against oxLDL-induced endothelial damage by suppressing ROS/NFκB-mediated ICAM-1 and E-selectin expression via up-regulation of PI3K/Akt/Nrf2-dependent antioxidant enzyme expression.
authors.affiliation: Department of Health and Nutrition Biotechnology, Asia University, Taichung 413, Taiwan; Department of Medical Research, China Medical University Hospital, China Medical University, Taichung 404, Taiwan.
authors.forename: Chin-Shiu
authors.initials: CS
authors.lastname: Huang
authors.affiliation: Department of Nutrition, China Medical University, Taichung 404, Taiwan.
authors.forename: Ai-Hsuan
authors.initials: AH
authors.lastname: Lin
authors.affiliation: Department of Nutrition, China Medical University, Taichung 404, Taiwan.
authors.forename: Ting-Chun
authors.initials: TC
authors.lastname: Yang
authors.affiliation: School of Nutrition, Chung Shan Medical University, Taichung 402, Taiwan.
authors.forename: Kai-Li
authors.initials: KL
authors.lastname: Liu
authors.affiliation: Department of Nutrition, China Medical University, Taichung 404, Taiwan. Electronic address: chenhw@mail.cmu.edu.tw.
authors.forename: Haw-Wen
authors.initials: HW
authors.lastname: Chen
authors.affiliation: Department of Health and Nutrition Biotechnology, Asia University, Taichung 413, Taiwan; Department of Nutrition, China Medical University, Taichung 404, Taiwan. Electronic address: cklii@mail.cmu.edu.tw.
authors.forename: Chong-Kuei
authors.initials: CK
authors.lastname: Lii
mesh_terms: D000975:Antioxidants / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008077:Lipoproteins, LDL / Q000037:antagonists & inhibitors / Q000633:toxicity*; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000096:biosynthesis*; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009285:Naphthoquinones / Q000494:pharmacology*; D058539:Phosphatidylinositol 3-Kinase / Q000096:biosynthesis*; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
chemical_list: D000975:Antioxidants; D008077:Lipoproteins, LDL; D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; C495635:NFE2L2 protein, human; D009285:Naphthoquinones; C099252:oxidized low density lipoprotein; C016101:shikonin; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt
keywords: Adhesion molecules; Antioxidant defense; Nuclear factor erythroid 2-related factor 2 (Nrf2); Nuclear factor-kappaB (NFκB); Oxidized LDL; Shikonin