Macrophage apoptosis exerts divergent effects on atherogenesis as a function of lesion stage.
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.


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.
Gautier
Emmanuel L
EL
INSERM U939, Hôpital de Pitié, Paris, France.
Huby
Thierry
T
Witztum
Joseph L
JL
Ouzilleau
Betty
B
Miller
Elizabeth R
ER
Saint-Charles
Flora
F
Aucouturier
Pierre
P
Chapman
M John
MJ
Lesnik
Philippe
P
D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D017209:Apoptosis / Q000276:immunology*; D001158:Arteries / Q000276:immunology / Q000473:pathology; D001167:Arteritis / Q000276:immunology* / Q000473:pathology*; D050197:Atherosclerosis / Q000276:immunology* / Q000473:pathology*; D001323:Autoantibodies / Q000097:blood / Q000276:immunology; D053148:Caspase 3 / Q000378:metabolism; D000939:Epitopes / Q000276:immunology / Q000378:metabolism; D019254:Genes, bcl-2 / Q000235:genetics; D006801:Humans; D008264:Macrophages / Q000473:pathology* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010084:Oxidation-Reduction; D010743:Phospholipids / Q000276:immunology / Q000378:metabolism; D019076:Transgenes / Q000502:physiology
D001057:Apolipoproteins E; D001323:Autoantibodies; D000939:Epitopes; D010743:Phospholipids; C505409:Casp3 protein, mouse; D053148:Caspase 3