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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2002;22:1712.)
© 2002 American Heart Association, Inc.

Atherosclerosis

Lipid Accumulation in Smooth Muscle Cells Under LDL Loading Is Independent of LDL Receptor Pathway and Enhanced by Hypoxic Conditions

Youichiro Wada; Akira Sugiyama; Takashi Yamamoto; Makoto Naito; Noriko Noguchi; Shinji Yokoyama; Maki Tsujita; Yoshiki Kawabe; Mika Kobayashi; Akashi Izumi; Takahide Kohro; Toshiya Tanaka; Hirokazu Taniguchi; Hidenori Koyama; Ken-ichi Hirano; Shizuya Yamashita; Yuji Matsuzawa; Etsuo Niki; Takao Hamakubo; Tatsuhiko Kodama

From the Department of Molecular Biology and Medicine (Y.W., A.S., M.K., A.I., T. Kohro, T.H., T. Kodama) and the Department of Genome Science (N.N., H.T.), Research Center for Advanced Science and Technology, University of Tokyo; the Division of Cellular and Molecular Pathology (T.Y., M.N.), Niigata University Graduate School of Medical and Dental Sciences, Niigata; the Department of Biochemistry, Cell Biology and Metabolism (S.Y., M.T.), Nagoya City University Graduate School of Medical Sciences, Nagoya; Research Center (T.T.), Research and Development, Grelan Pharmaceuticals Co, Ltd, Tokyo; Human Stress Signal Center (E.N.) and the Department of Metabolism, Endocrinology, and Molecular Medicine (H.K.), Osaka City University Graduate School of Medicine, and the Department of Internal Medicine and Molecular Science (K.H., S.Y., Y.M.), Osaka University Graduate School of Medicine, Osaka; and Chugai Pharmaceutical Co, Ltd (Y.K.), Shizuoka; Japan.

Correspondence to Tatsuhiko Kodama, Department of Molecular Biology and Medicine, Research Center for Advanced Science and Technology (#35), University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo 153-0061, Japan. E-mail kodama{at}med.rcast.u-tokyo.ac.jp

Abstract

Objective— The effect of a variety of hypoxic conditions on lipid accumulation in smooth muscle cells (SMCs) was studied in an arterial wall coculture and monocultivation model.

Methods and Results— Low density lipoprotein (LDL) was loaded under various levels of oxygen tension. Oil red O staining of rabbit and human SMCs revealed that lipid accumulation was greater under lower oxygen tension. Cholesterol esters were shown to accumulate in an oxygen tension–dependent manner by high-performance liquid chromatographic analysis. Autoradiograms using radiolabeled LDL indicated that LDL uptake was more pronounced under hypoxia. This result holds in the case of LDL receptor–deficient rabbit SMCs. However, cholesterol biosynthesis and cellular cholesterol release were unaffected by oxygen tension.

Conclusions— Hypoxia significantly increases LDL uptake and enhances lipid accumulation in arterial SMCs, exclusive of LDL receptor activity. Although the molecular mechanism is not clear, the model is useful for studying lipid accumulation in arterial wall cells and the difficult-to-elucidate events in the initial stage of atherogenesis.

Key Words: smooth muscle cells • LDL • hypoxia • cholesteryl ester

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