BACKGROUND: Because apoptotic cell clearance appears to be defective in advanced compared with early atherosclerotic plaques, macrophage apoptosis may differentially affect plaque progression as a function of lesion stage. METHODS AND RESULTS: We first evaluated the impact of targeted protection of macrophages against apoptosis at both early and advanced stages of atherosclerosis. Increased resistance of macrophages to apoptosis in early atherosclerotic lesions was associated with increased plaque burden; in contrast, it afforded protection against progression to advanced lesions. Conversely, sustained induction of apoptosis in lesional macrophages of advanced lesions resulted in a significant increase in lesion size. Such enhanced lesion size occurred as a result not only of apoptotic cell accumulation but also of elevated chemokine expression and subsequent intimal recruitment of circulating monocytes. CONCLUSIONS: Considered together, our data suggest that macrophage apoptosis is atheroprotective in fatty streak lesions, but in contrast, defective clearance of apoptotic debris in advanced lesions favors arterial wall inflammation and enhanced recruitment of monocytes, leading to enhanced atherogenesis.
BACKGROUND: Because apoptotic cell clearance appears to be defective in advanced compared with early atherosclerotic plaques, macrophage apoptosis may differentially affect plaque progression as a function of lesion stage. METHODS AND RESULTS: We first evaluated the impact of targeted protection of macrophages against apoptosis at both early and advanced stages of atherosclerosis. Increased resistance of macrophages to apoptosis in early atherosclerotic lesions was associated with increased plaque burden; in contrast, it afforded protection against progression to advanced lesions. Conversely, sustained induction of apoptosis in lesional macrophages of advanced lesions resulted in a significant increase in lesion size. Such enhanced lesion size occurred as a result not only of apoptotic cell accumulation but also of elevated chemokine expression and subsequent intimal recruitment of circulating monocytes. CONCLUSIONS: Considered together, our data suggest that macrophage apoptosis is atheroprotective in fatty streak lesions, but in contrast, defective clearance of apoptotic debris in advanced lesions favors arterial wall inflammation and enhanced recruitment of monocytes, leading to enhanced atherogenesis.
Authors: Christian Weber; Svenja Meiler; Yvonne Döring; Miriam Koch; Maik Drechsler; Remco T A Megens; Zuzanna Rowinska; Kiril Bidzhekov; Caroline Fecher; Eliana Ribechini; Marc A M J van Zandvoort; Christoph J Binder; Ivett Jelinek; Mihail Hristov; Louis Boon; Steffen Jung; Thomas Korn; Manfred B Lutz; Irmgard Förster; Martin Zenke; Thomas Hieronymus; Tobias Junt; Alma Zernecke Journal: J Clin Invest Date: 2011-07 Impact factor: 14.808
Authors: Vladimir R Babaev; Richard R Whitesell; Liying Li; MacRae F Linton; Sergio Fazio; James M May Journal: Free Radic Biol Med Date: 2010-10-23 Impact factor: 7.376