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(Circulation. 2009;119:1795-1804.)
© 2009 American Heart Association, Inc.

Vascular Medicine

Macrophage Apoptosis Exerts Divergent Effects on Atherogenesis as a Function of Lesion Stage

Emmanuel L. Gautier, PhD; Thierry Huby, PhD; Joseph L. Witztum, MD; Betty Ouzilleau, BS; Elizabeth R. Miller, BS; Flora Saint-Charles, MSc; Pierre Aucouturier, PhD; M. John Chapman, PhD; Philippe Lesnik, PhD

From INSERM UMR-S939, Hôpital de la Pitié (E.L.G., T.H., B.O., F.S.-C., M.J.C., P.L.), UPMC University Paris (E.L.G., T.H., B.O., F.S.-C., P.A., M.J.C., P.L.), AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Service d’Endocrinologie-Métabolisme (T.H., M.J.C., P.L.), and INSERM UMR S 938, Hôpital St-Antoine (P.A.), Paris, France, and Department of Medicine, University of California San Diego, La Jolla (J.L.W., E.R.M.).

Correspondence to Dr Philippe Lesnik, INSERM U939, Hôpital de la Pitié, 83 Bd de l’hôpital, 75651 Paris 13, France. E-mail philippe.lesnik{at}upmc.fr

Received July 11, 2008; accepted February 2, 2009.

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.

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CLINICAL PERSPECTIVE

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Clinical Summaries
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