Published online before print April 12, 2004, doi: 10.1161/01.CIR.0000125526.91945.AE
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(Circulation. 2004;109:2001-2008.)
© 2004 American Heart Association, Inc.
Basic Science Reports |
Caspase-3 and Tissue Factor Expression in Lipid-Rich Plaque Macrophages
Evidence for Apoptosis as Link Between Inflammation and Atherothrombosis
From the Cardiovascular Institute/Cardiovascular Biology Research Laboratory (R.H., C.V., I.C., J.T.F., V.F., J.J.B.), Institute for Gene Therapy and Molecular Medicine (B.V.S., M.S., F.E.C.), and Department of Pathology (J.T.F.), Mount Sinai School of Medicine, New York, NY; and Medizinische Klinik und Poliklinik II, Herzzentrum des Universitätsklinikums Bonn (G.B., B.L.), University of Bonn, Bonn, Germany.
Correspondence to Valentin Fuster, MD, PhD, Cardiovascular Institute, One Gustave L. Levy Place, Box 1030, New York, NY 10029-6574. E-mail valentin.fuster{at}mssm.edu
Received February 11, 2002; de novo received October 1, 2003; revision received January 5, 2004; accepted January 12, 2004.
Background— Macrophages associated with arterial wall lipid deposition contribute to inflammatory processes. Tissue factor (TF) has been implicated in the thrombogenicity of atherosclerotic plaques. Intimal cells undergoing apoptosis have been postulated as a source for TF. However, there is only limited knowledge of cell type, plaque component, and conditions associated with TF expression and apoptosis. We examined the hypothesis that macrophages exposed to conditions of lipid-rich plaque undergo apoptosis and express TF.
Methods and Results— In human carotid (n=15) and coronary (n=6) atherosclerotic plaques, TF and caspase-3 mRNA and protein expression (evaluated by in situ hybridization and immunohistochemistry) were increased significantly in lipid-rich compared with fibrous plaque components (P<0.01) and correlated with high macrophage content (P<0.05). Double-labeling studies demonstrated colocalization of TF and active caspase-3. In hyperlipidemic mice, expression of TF and active caspase-3 was observed simultaneously and colocalized in neointimal macrophages after arterial injury. In neointima of normolipidemic animals, TF and active caspase-3 were absent after arterial injury. In monocytes cultured in the presence of oxidized LDL, strong induction and colocalization of TF and active caspase-3 were found compared with baseline (P<0.05). Both antigens were significantly decreased after cotreatment with a caspase inhibitor (P<0.05) and were absent in untreated control cells.
Conclusions— The expression of TF as the primary cell-associated activator of the coagulation pathway proves to be closely related to macrophages undergoing apoptosis in conditions of lipid-rich plaque, pointing to a key role of lipid content and inflammatory cell viability in determining plaque thrombogenicity.
Key Words: lipids • inflammation • apoptosis • thrombosis
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