title: Cilostazol prevents remnant lipoprotein particle-induced monocyte adhesion to endothelial cells by suppression of adhesion molecules and monocyte chemoattractant protein-1 expression via lectin-like receptor for oxidized low-density lipoprotein receptor activation.
abstract: This study shows cilostazol effect to prevent remnant lipoprotein particle (RLP)-induced monocyte adhesion to human umbilical vein endothelial cells (HUVECs). Upon incubation of HUVECs with RLP (50 microg/ml), adherent monocytes significantly increased by 3.3-fold with increased cell surface expression of vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1, E-selectin, and monocyte chemoattractant protein-1 (MCP-1). Cilostazol ( approximately 1-100 microM) concentration dependently repressed these variables as did (E)3-[(4-t-butylphenyl)sulfonyl]-2-propenenitrile (BAY 11-7085) (10 microM), a specific nuclear factor-kappaB (NF-kappaB) inhibitor. Cilostazol effects were significantly antagonized by iberiotoxin (1 microM), a maxi-K channel blocker. RLP significantly increased expression of lectin-like receptor for oxidized low-density lipoprotein (LDL) (LOX-1) receptor protein. Upon transfection with antisense LOX-1 oligodeoxynucleotide (As-LOX-1), LOX-1 receptor expression was reduced, whereas HUVECs with sense LOX-1 oligodeoxynucleotide did express high LOX-1 receptor. RLP-stimulated superoxide and tumor necrosis factor-alpha levels were significantly lowered with decreased expression of VCAM-1 and MCP-1 by transfection with As-LOX-1 as did polyinosinic acid (10 microg/ml, a LOX-1 receptor inhibitor). RLP significantly degraded inhibitory kappaBalpha in the cytoplasm and activated nuclear factor-kappaB (NF-kappaB) p65 in the nucleus of HUVECs with increased luciferase activity of NF-kappaB, all of which were reversed by cilostazol (10 microM), BAY 11-7085, and polyinosinic acid. Together, cilostazol suppresses RLP-stimulated increased monocyte adhesion to HUVECs by suppression of LOX-1 receptor-coupled NF-kappaB-dependent nuclear transcription via mediation of the maxi-K channel opening.
authors.affiliation: Department of Pharmacology, College of Medicine, Pusan National University, Ami-Dong 1-Ga, SeoGu, Busan 602-739, Korea. kwhong@pusan.ac.kr
authors.forename: So Youn
authors.initials: SY
authors.lastname: Park
authors.forename: Jeong Hyun
authors.initials: JH
authors.lastname: Lee
authors.forename: Yong Ki
authors.initials: YK
authors.lastname: Kim
authors.forename: Chi Dae
authors.initials: CD
authors.lastname: Kim
authors.forename: Byung Yong
authors.initials: BY
authors.lastname: Rhim
authors.forename: Won Suk
authors.initials: WS
authors.lastname: Lee
authors.forename: Ki Whan
authors.initials: KW
authors.lastname: Hong
mesh_terms: D002118:Calcium / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D015815:Cell Adhesion Molecules / Q000032:analysis*; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000032:analysis*; D002784:Cholesterol / Q000494:pharmacology; D000077407:Cilostazol; D042783:Endothelial Cells / Q000166:cytology*; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D051036:Large-Conductance Calcium-Activated Potassium Channels; D008074:Lipoproteins / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D009000:Monocytes / Q000502:physiology*; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D024681:Potassium Channels, Calcium-Activated / Q000187:drug effects; D011973:Receptors, LDL / Q000378:metabolism*; D051131:Receptors, Oxidized LDL; D051127:Scavenger Receptors, Class E; D013481:Superoxides / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology*; D014280:Triglycerides / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D015815:Cell Adhesion Molecules; D018932:Chemokine CCL2; D020672:I-kappa B Proteins; D051036:Large-Conductance Calcium-Activated Potassium Channels; D008074:Lipoproteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C495137:OLR1 protein, human; D024681:Potassium Channels, Calcium-Activated; D011973:Receptors, LDL; D051131:Receptors, Oxidized LDL; D051127:Scavenger Receptors, Class E; D013777:Tetrazoles; D014280:Triglycerides; D014409:Tumor Necrosis Factor-alpha; C112017:remnant-like particle cholesterol; D013481:Superoxides; D000072000:NF-KappaB Inhibitor alpha; D002784:Cholesterol; D000077407:Cilostazol; D002118:Calcium