doi: 10.1161/hq0701.092145
© 2001 American Heart Association, Inc.
Vascular Biology |
Apoptotic Death of Inflammatory Cells in Human Atheroma
From the Division of Pathology II, Faculty of Health Sciences, Linköping University, Linköping, Sweden (W.L., X.-M.Y.); the Department of Pathology, Gade Institute, University of Bergen, Bergen, Norway (H.D.); and the James Graham Brown Cancer Center, University of Louisville, Louisville, Ky (J.W.E.).
Correspondence to Wei Li, MD, PhD, Division of Pathology II, Linköping University Hospital, S-581 85 Linköping, Sweden. E-mail weili{at}pat.liu.se
Abstract—Although the accumulation of cholesterol and other lipidic material is unquestionably important in atherogenesis, the reasons why this material progressively accumulates, rather than being effectively cleared by phagocytic cells such as macrophages, are not completely understood. We hypothesize that atheromatous lesions may represent "death zones" that contain toxic materials such as oxysterols and in which monocytes/macrophages become dysfunctional and apoptotic. Indeed, cathepsins B and L, normally confined to the lysosomal compartment, are present in the cytoplasm and nuclei of apoptotic (caspase-3–positive) macrophages within human atheroma. The possible involvement of oxysterols is suggested by experiments in which cultured U937 and THP-1 cells exposed to 7-oxysterols similarly undergo marked lysosomal destabilization, caspase-3 activation, and apoptosis. Like macrophages within atheroma, intralysosomal cathepsins B and L are normally present in the cytoplasm and nuclei of these oxysterol-exposed cells. Lysosomal destabilization, cathepsin release, and apoptosis may be causally related, because inhibitors of cathepsins B and L suppress oxysterol-induced apoptosis. Thus, toxic materials such as 7-oxysterols in atheroma may impair the clearance of cholesterol and other lipidic material by fostering the apoptotic death of phagocytic cells, thereby contributing to further development of atherosclerotic lesions.
Key Words: atherosclerosis • apoptosis • lysosomal enzymes • oxysterols • plaque instability
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