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(Circulation. 2004;109:1022-1028.)
© 2004 American Heart Association, Inc.

Basic Science Reports

Remnant Lipoprotein Particles Induce Apoptosis in Endothelial Cells by NAD(P)H Oxidase–Mediated Production of Superoxide and Cytokines via Lectin-Like Oxidized Low-Density Lipoprotein Receptor-1 Activation

Prevention by Cilostazol

Hwa Kyoung Shin, PhD; Yong Ki Kim, MD, PhD; Ki Young Kim, PhD; Jeong Hyun Lee, MS; Ki Whan Hong, MD, PhD

From the Departments of Pharmacology (H.K.S., K.Y.K., J.H.L., K.W.H.) and Internal Medicine (Y.K.K.), College of Medicine, Pusan National University, Busan, Korea.

Correspondence to Ki Whan Hong, MD, Department of Pharmacology, College of Medicine, Pusan National University, Ami-Dong 1-Ga, Seo-Gu, Pusan 602-739, Korea. E-mail kwhong{at}pusan.ac.kr

Received August 8, 2003; revision received October 30, 2003; accepted October 31, 2003.

Background— Remnant lipoprotein particles (RLPs), products of lipolytic degradation of triglyceride-rich lipoprotein derived from VLDL, exert atherogenesis. In this study, we observed how RLPs induced cytotoxicity in human umbilical vein endothelial cells (HUVECs) and cilostazol prevented cell death.

Methods and Results— RLPs were isolated from the plasma of hyperlipidemic patients by use of an immunoaffinity gel mixture of anti–apolipoprotein A-1 and anti–apolipoprotein B-100 monoclonal antibodies. RLPs (50 µg/mL) significantly increased superoxide formation in HUVECs associated with elevated gp91phox mRNA and protein expression and Rac1 translocation, accompanied by increased production of tumor necrosis factor (TNF)- and interleukin-1ß, DNA fragmentation, and cell death. Cilostazol (1 to 100 µmol/L) significantly suppressed not only NAD(P)H oxidase–dependent superoxide production but also TNF- and interleukin-1ß release and restored viability. RLPs activated a lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), which was not inhibited by cilostazol. Treatment of HUVECs with monoclonal antibody for LOX-1 attenuated RLP-mediated production of superoxide, TNF-, and interleukin-1ß and DNA fragmentation.

Conclusions— RLPs stimulated NAD(P)H oxidase–dependent superoxide formation and induction of cytokines in HUVECs via activation of LOX-1, consequently leading to reduction in cell viability with DNA fragmentation, and cilostazol exerts a cell-protective effect by suppressing these variables.

Key Words: apoptosis • atherosclerosis • lipoproteins • superoxide

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