title: Isothiocyanates protect against oxidized LDL-induced endothelial dysfunction by upregulating Nrf2-dependent antioxidation and suppressing NFκB activation.
abstract: METHODS
  Oxidative stress plays a pivotal role in the pathophysiology of cardiovascular diseases. Oxidized low-density lipoprotein (oxLDL) is a key contributor to atherogenesis through multiple mechanisms. In this study, we investigated the protection by three structurally related isothiocyanates, i.e., sulforaphane (SFN), benzyl isothiocyanate (BITC), and phenethyl isocyanate (PEITC), against oxLDL-induced leukocyte adhesion to vascular endothelium and the mechanism involved.
  
  
  RESULTS
  The protection against oxLDL-induced endothelial dysfunction by isothiocyanates was studied in human umbilical vein endothelial cells (HUVECs). oxLDL increased reactive oxygen species (ROS) production, stimulated nuclear factor-kappaB (NFκB) activation, and enhanced intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), and E-selectin expression in HUVECs, which led to promotion of monocyte adhesion to HUVECs. Treatment with SFN, BITC, and PEITC (0-10 μM) dose-dependently induced heme oxygenase (HO)-1, glutamate cysteine ligase (GCL) catalytic and modifier subunit expression, intracellular glutathione content, and antioxidant response element (ARE)-luciferase reporter activity. SFN, BITC, and PEITC pretreatment reversed oxLDL-induced ROS production, NFκB nuclear translocation, κB-reporter activity, ICAM-1, VCAM-1, and E-selectin expression, and monocyte adhesion to endothelial cells. Both heme oxygenase 1 (HO-1) and nuclear factor erythroid 2-related factor 2 (Nrf2) knockdown attenuated the isothiocyanate inhibition of oxLDL-induced ROS production, κB-reporter activity, and adhesion molecule expression.
  
  
  CONCLUSIONS
  SFN, BITC, and PEITC protect against oxLDL-induced endothelial damage by upregulating Nrf2-dependent HO-1 and GCL expression, which leads to inhibition of NFκB activation and ICAM-1, VCAM-1, and E-selectin expression.
authors.affiliation: Department of Health and Nutrition Biotechnology, Asia University, Taichung, Taiwan.
authors.forename: Chin-Shiu
authors.initials: CS
authors.lastname: Huang
authors.forename: Ai-Hsuan
authors.initials: AH
authors.lastname: Lin
authors.forename: Cheng-Tzu
authors.initials: CT
authors.lastname: Liu
authors.forename: Chia-Wen
authors.initials: CW
authors.lastname: Tsai
authors.forename: Ing-Shr
authors.initials: IS
authors.lastname: Chang
authors.forename: Haw-Wen
authors.initials: HW
authors.lastname: Chen
authors.forename: Chong-Kuei
authors.initials: CK
authors.lastname: Lii
mesh_terms: D061745:Antioxidant Response Elements / Q000187:drug effects; D000975:Antioxidants / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D019040:E-Selectin / Q000235:genetics / Q000378:metabolism; D005721:Glutamate-Cysteine Ligase / Q000235:genetics / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D017879:Isothiocyanates / Q000494:pharmacology*; D007962:Leukocytes / Q000187:drug effects / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000009:adverse effects*; D051267:NF-E2-Related Factor 2 / Q000235:genetics* / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013454:Sulfoxides; D015854:Up-Regulation; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism
chemical_list: D000975:Antioxidants; D019040:E-Selectin; C573420:ICAM1 protein, human; D017879:Isothiocyanates; D008077:Lipoproteins, LDL; D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; C495635:NFE2L2 protein, human; D017382:Reactive Oxygen Species; C546936:SELE protein, human; D013454:Sulfoxides; D019010:Vascular Cell Adhesion Molecule-1; C099252:oxidized low density lipoprotein; D018799:Intercellular Adhesion Molecule-1; C031403:benzyl isothiocyanate; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; D005721:Glutamate-Cysteine Ligase; C016766:sulforaphane
keywords: Adhesion molecules; Glutamate cysteine ligase; Heme oxygenase 1; Isothiocyanates; Nuclear factor erythroid 2-related factor 2 (Nrf2); Nuclear factor-kappaB (NFκB); Oxidized LDL