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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2001;21:1801.)
© 2001 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

In Vivo Complex Formation of Oxidized ₁-Antitrypsin and LDL

Shinichi Mashiba; Youichiro Wada; Motohiro Takeya; Akira Sugiyama; Takao Hamakubo; Akio Nakamura; Noriko Noguchi; Etsuo Niki; Akashi Izumi; Mika Kobayashi; Kazuo Uchida; Tatsuhiko Kodama

From Ikagaku Co Ltd, Kyoto (S.M., K.U.); the Department of Molecular Biology and Medicine (Y.W., A.S., T.H., A.I., M.K., T.K.) and the Department of Genome Science (A.N., N.N.), Research Center for Advanced Science and Technology, University of Tokyo; and the Second Department of Pathology (M.T.), Kumamoto University School of Medicine, Kumamoto, and the Human Stress Signal Center (E.N.), Osaka, Japan. The first 2 authors contributed equally to this work.

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—— An inactivated form of ₁-antitrypsin (AT) and LDL coelutes in gel permeation chromatography. To characterize and to quantify the amount of this fraction of AT, a monoclonal antibody was established against chloramine T–oxidized AT and named OxAT-4. OxAT-4 recognized the oxidatively modified AT, including hexylaldehyde- or 4-hydroxy-2-nonenal–modified AT, but neither normal active AT nor trypsin/AT complex. Comigration of apoB and oxidized AT was demonstrated by Western blotting analysis of AT-LDL by means of anti-apoB monoclonal antibody and OxAT-4. A complex of oxidized AT and LDL (AT-LDL) was isolated from human plasma LDL by affinity column with an OxAT-4 antibody–coated carrier. AT-LDL was degraded 4 times more effectively by mouse peritoneal macrophages, but this was not mediated by scavenger receptor class A type I. Localization of AT-LDL was detected in human atherosclerotic lesions of the coronary artery, but distribution of it was not completely identical to that of macrophages. In situ hybridization revealed AT expression by macrophages, which were present in intimal layers of the coronary artery. From these findings, we concluded that AT is produced and oxidized by macrophages, then attached to LDL in the intimal layer of the arterial wall. Although AT-LDL that escapes into the blood stream can be cleared by hepatocytes, the remaining AT-LDL may be taken up by macrophages and contribute to the lipid accumulation in arterial wall cells as the early stage of atherogenesis.

Key Words: ₁-antitrypsin • LDL • complex • monoclonal antibody • macrophage

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