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 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-κB (NF-κB) 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-α 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 κBα in the cytoplasm and activated nuclear factor-κB (NF-κB) p65 in the nucleus of HUVECs with increased luciferase activity of NF-κB, 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-κB-dependent nuclear transcription via mediation of the maxi-K channel opening.
Footnotes
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doi:10.1124/jpet.104.077826.
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ABBREVIATIONS: Ox-LDL, oxidized low-density lipoprotein; RLP, remnant lipoprotein particle(s); VLDL, very low-density lipoprotein; LOX-1, lectin-like receptor for oxidized-low-density lipoprotein; TNF-α, tumor necrosis factor-α; VCAM-1, vascular cell adhesion molecule-1; ICAM-1, intercellular adhesion molecule-1; MCP-1, monocyte chemoattractant protein-1; As-LOX-1, antisense-lectin-like receptor for oxidized-low-density lipoprotein; IκBα, inhibitory κBα; NF-κB, nuclear factor-κB; HUVEC, human umbilical vein endothelial cell; ELISA, enzyme-linked immunosorbent assay; LDL, low density lipoprotein; WT, wild-type; BAY 11-7085, (E)3-[(4-t-butylphenyl)sulfonyl]-2-propenenitrile.
- Received September 13, 2004.
- Accepted November 1, 2004.
- The American Society for Pharmacology and Experimental Therapeutics
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