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Brief report: increased apoptosis in advanced atherosclerotic lesions of Apoe-/- mice lacking macrophage Bcl-2.

ABSTRACT: Macrophage apoptosis plays important roles in atherosclerosis. Bcl-2 is a key cell survival molecule, but its role in macrophage apoptosis in atherosclerosis is not known. The goal herein was to determine the effect of macrophage-targeted deletion of Bcl-2 on macrophage apoptosis in atherosclerotic lesions of Apoe(-/-) mice.Bcl2(flox)-LysMCre mice were created as a model of macrophage Bcl-2 deficiency. Macrophages from these mice were more susceptible to apoptosis than those from control Bcl2(WT)-LysMCre mice. The mice were bred onto the Apoe(-/-) background and fed a Western-type diet for 4 or 10 weeks. Apoptotic cells were equally very rare in the lesions of both groups of the 4-week-diet mice, and there was no difference in lesion area. However, Bcl2(flox)-LysMCre;Apoe(-/-) plaques from the 10-week-diet protocol had a 40% to 45% increase in apoptotic cells and, in female mice, a approximately 25% increase in plaque necrosis (P<0.05) compared with Bcl2(WT)-LysMCre lesions.Macrophage Bcl-2 plays a protective role against macrophage apoptosis specifically in advanced atherosclerotic lesions of Apoe(-/-) mice.

SUBMITTER: Thorp E

PROVIDER: S-EPMC2731712 | biostudies-literature | 2009 Feb

REPOSITORIES: biostudies-literature

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Brief report: increased apoptosis in advanced atherosclerotic lesions of Apoe-/- mice lacking macrophage Bcl-2.

Thorp Edward E Li Yankun Y Bao Liping L Yao Pin Mei PM Kuriakose George G Rong James J Fisher Edward A EA Tabas Ira I

Arteriosclerosis, thrombosis, and vascular biology 20081106 2

<h4>Objective</h4>Macrophage apoptosis plays important roles in atherosclerosis. Bcl-2 is a key cell survival molecule, but its role in macrophage apoptosis in atherosclerosis is not known. The goal herein was to determine the effect of macrophage-targeted deletion of Bcl-2 on macrophage apoptosis in atherosclerotic lesions of Apoe(-/-) mice.<h4>Methods and results</h4>Bcl2(flox)-LysMCre mice were created as a model of macrophage Bcl-2 deficiency. Macrophages from these mice were more susceptibl ...[more]

PMID: 18988889

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Project description:BackgroundReprogramming of monocytes and macrophage manifests in hyperinflammatory responses and chronification of inflammation in atherosclerosis. Recent studies focused on epigenetic, transcriptional, and metabolic alterations that characterize trained immunity. However, the underlying effector mechanisms driving the hyperinflammatory response of reprogrammed macrophages remain unclear. We hypothesized that the plasma membrane of atherosclerotic lesion macrophages undergoes reprogramming to maintain inflammarafts, enlarged lipid rafts (LR) serving as a platform for assembly of inflammatory receptor complexes.MethodsSingle-cell suspensions from the aortae of Western diet-fed Ldlr-/- mice were gated for BODIPY-high foamy and BODIPY-low nonfoamy F4/80 macrophages by flow cytometry. Inflammarafts were characterized by increased levels of LR, TLR4 (toll-like receptor-4) localization to LR, TLR4 dimers, and the proximity between TLR2, TLR1, and CD36. In a cellular model of trained immunity, LR, TLR4 dimers, and the inflammatory response were measured in bone marrow-derived macrophages subjected to a 24-hour treatment with LPS (lipopolysaccharide) or OxLDL (oxidized low-density lipoprotein), followed by a 6-day wash-out period.ResultsNonfoamy macrophages, which constituted ≈40% of macrophages in atherosclerotic lesions, expressed significantly higher levels of LR and TLR4 dimers, as well as proximity ligation signals for TLR4-LR, TLR2-CD36, and TLR2-TLR1 complexes, compared with foamy macrophages. These inflammaraft measures associated, to a different degree, with plasma cholesterol and inflammatory cytokines, as well as the size of the atherosclerotic lesions and necrotic cores. The bone marrow-derived macrophages trained with LPS simulated nonfoamy atherosclerotic lesion macrophages and continued to express inflammarafts and inflammatory genes for 6 days after LPS removal and displayed a hyperinflammatory response to Pam3CSK4, a TLR2/TLR1 agonist. OxLDL-exposed, lipid-laden macrophages did not express inflammarafts.ConclusionsOur data support the hypothesis that persistent inflammarafts in nonfoamy macrophages in atherosclerotic lesions serve as effectors of macrophage reprogramming into a hyperinflammatory phenotype.

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Brief report: increased apoptosis in advanced atherosclerotic lesions of Apoe-/- mice lacking macrophage Bcl-2.

Publications

Brief report: increased apoptosis in advanced atherosclerotic lesions of Apoe-/- mice lacking macrophage Bcl-2.

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