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Cardiovasc Res. 2015 Oct 1;108(1):111-23. doi: 10.1093/cvr/cvv177. Epub 2015 Jun 19.

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

Author information

1
INSERM, UMR_S U1166, Integrative Biology of Atherosclerosis Team, Hôpital de la Pitié, Pavillon Benjamin Delessert, 83 Boulevard de L'hôpital, Paris F-75013, France Sorbonne Universités, UPMC Université Paris 06, UMR_S 1166, ICAN, Integrative Biology of Atherosclerosis Team, Paris F-75005, France.
2
INSERM, UMR_S U1166, Integrative Biology of Atherosclerosis Team, Hôpital de la Pitié, Pavillon Benjamin Delessert, 83 Boulevard de L'hôpital, Paris F-75013, France Institute of Cardiometabolism and Nutrition, ICAN, AP-HP, Pitié-Salpêtrière Hospital, Paris F-75013, France.
3
Atherosclerosis Group, ANZAC Research Institute, University of Sydney and Concord Hospital, Sydney, Australia.
4
INSERM, UMR_S U1166, Integrative Biology of Atherosclerosis Team, Hôpital de la Pitié, Pavillon Benjamin Delessert, 83 Boulevard de L'hôpital, Paris F-75013, France Sorbonne Universités, UPMC Université Paris 06, UMR_S 1166, ICAN, Integrative Biology of Atherosclerosis Team, Paris F-75005, France Institute of Cardiometabolism and Nutrition, ICAN, AP-HP, Pitié-Salpêtrière Hospital, Paris F-75013, France.
5
INSERM, UMR_S U1166, Integrative Biology of Atherosclerosis Team, Hôpital de la Pitié, Pavillon Benjamin Delessert, 83 Boulevard de L'hôpital, Paris F-75013, France Sorbonne Universités, UPMC Université Paris 06, UMR_S 1166, ICAN, Integrative Biology of Atherosclerosis Team, Paris F-75005, France Institute of Cardiometabolism and Nutrition, ICAN, AP-HP, Pitié-Salpêtrière Hospital, Paris F-75013, France philippe.lesnik@upmc.fr emmanuel-laurent.gautier@inserm.fr.

Abstract

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.

KEYWORDS:

Apolipoprotein E; Apoptosis; Atherosclerosis; Cholesterol; Macrophage

PMID:
26092098
DOI:
10.1093/cvr/cvv177
[Indexed for MEDLINE]

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