Caspase-3 and Tissue Factor Expression in Lipid-Rich Plaque Macrophages: Evidence for Apoptosis as Link between Inflammation and Atherothrombosis

Randolph Hutter, Carolina Valdiviezo, Bernhard V. Sauter, Mikko Savontaus, Igor Chereshnev, Francine E. Carrick, Gerhard Bauriedel, Berndt Lüderitz, John T. Fallon, Valentin Fuster, Juan J. Badimon

Research output: Contribution to journalArticlepeer-review

111 Scopus citations


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.

Original languageEnglish
Pages (from-to)2001-2008
Number of pages8
Issue number16
StatePublished - 27 Apr 2004


  • Apoptosis
  • Inflammation
  • Lipids
  • Thrombosis


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