Bcl-x inactivation in macrophages accelerates progression of advanced atherosclerotic lesions in Apoe -/- Mice

Andrew I U Shearn, Virginie Deswaerte, Emmanuel L Gautier, Flora Saint-Charles, John Pirault, Laura Bouchareychas, Edmund B Rucker, III, Sophie Beliard, John Chapman, Wendy Jessup, Thierry Huby, Philippe Lesnik

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13 Citations (Scopus)

Abstract

Objective-: Bcl-x is the most abundantly expressed member of the Bcl-2 gene family in macrophages, but its role in macrophage apoptosis during atherogenesis is unknown. Methods And Results-: We previously reported dual pro-and antiatherogenic effects of macrophage survival in early versus advanced atherosclerotic lesions, respectively, potentially reflecting growing impairment of efferocytosis during plaque progression. Here, we specifically inactivated Bcl-x in macrophages and evaluated its impact on atherosclerotic lesion formation in Apoe mice at various stages of the disease. Bcl-x deficiency in macrophages increased their susceptibility to apoptosis, resulting in the depletion of tissue macrophages in vivo, including its major pool, Küppfer cells in the liver. We also observed increased cholesterol levels that were, however, not associated with any acceleration of early atherosclerotic plaque progression. This observation suggests that the atheroprotective effect of macrophage apoptosis at that stage of disease was counterbalanced by enhanced cholesterol levels. Bcl-x KO/Apoe mice exhibited significantly larger advanced lesions than control mice. These lesions showed vulnerable traits. Such enhanced lesion size may occur as a result not only of apoptotic cell accumulation but also of elevated cholesterol levels. Conclusion-: Modulation of macrophage resistance to apoptosis through targeted deletion of Bcl-x has a major impact on the entire macrophage cell population in the body, including Küpffer cells. Macrophage survival may, therefore, not only influence atherosclerotic plaque development and vulnerability but also cholesterol metabolism.
Original languageEnglish
Pages (from-to)1142-1149
Number of pages8
JournalArteriosclerosis, Thrombosis and Vascular Biology
Volume32
Issue number5
DOIs
Publication statusPublished - 1 May 2012
Externally publishedYes

Keywords

  • ABC transporter
  • Apoptosis
  • Atherosclerosis
  • Immune system
  • Macrophages

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