Promoting macrophage survival delays progression of pre-existing atherosclerotic lesions through macrophage-derived apoE

Aims: Macrophage apoptosis is a prominent feature of atherosclerosis, yet whether cell death-protected macrophages would favour the resolution of already established atherosclerotic lesions, and thus hold therapeutic potential, remains unknown.Methods and results: We irradiated then transplanted int...

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Bibliographic Details
Published in:Cardiovascular research 2015-09, Vol.108 (1), p.111-123
Main Authors: Bouchareychas, Laura, Pirault, John, Saint-Charles, Flora, Deswaerte, Virginie, Le Roy, Tiphaine, Jessup, Wendy, Giral, Philippe, Le Goff, Wilfried, Huby, Thierry, Gautier, Emmanuel, Lesnik, Philippe
Format: Article
Language:English
Subjects:
Animals
Antigens, Ly
Apolipoproteins E
Apoptosis
Atherosclerosis
Cell Survival
Cholesterol
Disease Progression
Life Sciences
Macrophages
Male
Mice
Proto-Oncogene Proteins c-bcl-2
Receptors, LDL
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Summary:Aims: Macrophage apoptosis is a prominent feature of atherosclerosis, yet whether cell death-protected macrophages would favour the resolution of already established atherosclerotic lesions, and thus hold therapeutic potential, remains unknown.Methods and results: We irradiated then transplanted into Apoe(-/-) or LDLr(-/-) recipient mice harbouring established atherosclerotic lesions, bone marrow cells from mice displaying enhanced macrophage survival through overexpression of the antiapoptotic gene hBcl-2 (Mø-hBcl2 Apoe(-/-) or Mø-hBcl2 Apoe(+/+) LDLr(-/-)). Both recipient mice exhibited decreased lesional apoptotic cell content and reduced necrotic areas when repopulated with Mø-hBcl2 mouse-derived bone marrow cells. In contrast, only LDLr(-/-) recipients showed a reduction in plasma cholesterol levels and in atherosclerotic lesions. The absence of significant reduction of plasma cholesterol levels in the context of apoE deficiency highlighted macrophage-derived apoE as key in both the regulation of plasma and tissue cholesterol levels and the progression of pre-existing lesion. Accordingly, hBcl2 expression in macrophages was associated with larger pools of Kupffer cells and Ly-6C(low) monocytes, both high producers of apoE. Additionally, increased Kupffer cells population was associated with improved clearance of apoptotic cells and modified lipoproteins.Conclusion: Collectively, these data show that promoting macrophage survival provides a supplemental source of apoE, which hinders pre-existing plaque progression.
ISSN:0008-6363
DOI:10.1093/cvr/cvv177