© 2001 by European Society of Cardiology
Copyright © 2000, European Society of Cardiology
Oxidized low density lipoprotein induces apoptosis via generation of reactive oxygen species in vascular smooth muscle cells
aGraduate Institute of Life Sciences, Chang Gung University College of Medicine, Tao-Yuan, Taiwan, ROC
bDepartment of Pharmacology, National Defense Medical Center, Taipei, Taiwan, ROC
cDepartment of Physiology and Pharmacology, Chang Gung University College of Medicine, 259 Wen Hwa 1Rd., Kwei-Shan, Tao-Yuan, Taiwan, ROC
* Corresponding author. Tel.: +11-886-3-3283016; fax: +11-886-3-3283031 ytlau{at}mail.cgu.edu.tw
Objective: Death of vascular smooth muscle cell (VSMC) induced by oxidized LDL (oxLDL) can occur by both necrosis and apoptosis which may contribute to plaque instability and rupture. Reactive oxygen species (ROS) induces apoptosis in VSMC and is involved in oxLDL action, we tested the hypothesis here that a coupling exists between ROS generation and apoptosis of oxLDL-treated VSMC. Methods: Cultured VSMC from rat aorta were treated with oxLDL, apoptosis and necrosis were distinguished by using FITC-annexin V label and propidium iodide stain, analyzed by flow cytometry. ROS generation of VSMCs was detected by the fluorescence intensity of DCF. Apoptosis was also determined by cleavage of procaspase-3. Results: OxLDL induced apoptosis (3 h) in a dose-dependent manner and reached maximum (with near-basal necrosis) at a concentration of 300 µg/ml. At this and lower (100 µg/ml) concentration, oxLDL, but not native LDL, stimulated ROS production rapidly (
5 min) and ROS level remained elevated for at least 45 min. Catalase and deferoxamine reduced both oxLDL-induced apoptosis and ROS generation. Superoxide dismutase and benzoic acid neither reduced the oxLDL-induced ROS generation nor inhibited apoptosis. Since oxLDL-induced ROS generation were inhibited by nordihydroguaiaretic acid and rotenone, lipoxygenase and mitochondrial pathways could be involved. In addition, catalase, deferoxamine, and N-acetylcysteine inhibited oxLDL-induced cleavage of procaspase-3 as well. Conclusions: ROS generation and apoptosis are tightly coupled in oxLDL-treated VSMCs. Antioxidants that reduced ROS level inhibited apoptosis, those that did not reduce ROS level were ineffective. Both mitochondrial and lipoxygenase activities may be involved.
KEYWORDS Apoptosis; Atherosclerosis; Free radicals; Lipoproteins; Smooth muscle
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