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INFLAMMATION AND IMMUNOPHARMACOLOGY

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

Department of Pharmacology (S.Y.P., J.H.L., C.D.K., B.Y.R., W.S.L., K.W.H.) and Internal Medicine (Y.K.K), College of Medicine, Pusan National University, Busan, Korea

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 µg/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 (1-100 µM) concentration dependently repressed these variables as did (E)3-[(4-t-butylphenyl)sulfonyl]-2-propenenitrile (BAY 11-7085) (10 µM), a specific nuclear factor-B (NF-B) inhibitor. Cilostazol effects were significantly antagonized by iberiotoxin (1 µM), 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- levels were significantly lowered with decreased expression of VCAM-1 and MCP-1 by transfection with As-LOX-1 as did polyinosinic acid (10 µg/ml, a LOX-1 receptor inhibitor). RLP significantly degraded inhibitory B in the cytoplasm and activated nuclear factor-B (NF-B) p65 in the nucleus of HUVECs with increased luciferase activity of NF-B, all of which were reversed by cilostazol (10 µM), BAY 11-7085, and polyinosinic acid. Together, cilostazol suppresses RLP-stimulated increased monocyte adhesion to HUVECs by suppression of LOX-1 receptor-coupled NF-B-dependent nuclear transcription via mediation of the maxi-K channel opening.

Address correspondence to: Dr. Ki Whan Hong, Department of Pharmacology, College of Medicine, Pusan National University, Ami-Dong 1-Ga, SeoGu, Busan 602-739, Korea. E-mail: kwhong{at}pusan.ac.kr

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