Phagocytosis in atherosclerosis: Molecular mechanisms and implications for plaque progression and stability

Schrijvers, Dorien M.; Meyer, Guido R.Y. De; Herman, Arnold G.; Martinet, Wim

doi:10.1016/j.cardiores.2006.09.005

Cited by 244 publications

(201 citation statements)

References 90 publications

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“…Macrophage dysfunction and accumulation initiates atherosclerosis and promotes lesion instability [45] . To determine the effect of betulin on macrophages in vivo, we performed immunofluorescence experiments on cryosections of the aortic sinus from different treatment groups of apoE -/-mice.…”

Section: Discussionmentioning

confidence: 99%

Betulin attenuates atherosclerosis in apoE−/− mice by up-regulating ABCA1 and ABCG1

et al. 2016

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Aim: Betulin is a pentacyclic triterpenoid isolated from the bark of yellow and white birch trees with anti-cancer and anti-malaria activities. In this study we examined the effects of betulin on atherosclerosis in apoE -/-mice and the underlying mechanisms. Methods: Murine macrophage RAW264.7 cells and human monocyte-derived THP-1 cells were tested. Foam cell formation was detected with Oil Red O staining. Cholesterol efflux was assessed using [3 H]-cholesterol efflux assay. The expression of ATP-binding cassette transporter A1 and G1 (ABCA1 and ABCG1) was examined using RT-PCR and Western-blotting. The ABCA1 promoter activity was evaluated using luciferase activity assay. Male apoE -/-mice fed on a high-fat-diet (HFD), and received betulin (20 and 40 mg·kg -1 ·d -1, ig) for 12 weeks. The macrophage content and ABCA1 expression in the aortic sinuses were evaluated with immunofluorescence staining. The hepatic, intestinal and fecal cholesterol were also analyzed in the mice. Results: In RAW264.7 cells, betulin (0.1-2.5 μg/mL) dose-dependently ameliorated oxLDL-induced cholesterol accumulation and enhanced cholesterol efflux. In both RAW264.7 and THP-1 cells, betulin increased the expression of ABCA1 and ABCG1 via suppressing the transcriptional repressors sterol-responsive element-binding proteins (SREBPs) that bound to E-box motifs in ABCA1 promoter, whereas E-box binding site mutation markedly attenuated betulin-induced ABCA1 promoter activity. In HFD-fed apoE -/-mice, betulin administration significantly reduced lesions in en face aortas and aortic sinuses. Furthermore, betulin administration significantly increased ABCA1 expression and suppressed macrophage positive areas in the aortic sinuses. Moreover, betulin administration improved plasma lipid profiles and enhanced fecal cholesterol excretion in the mice. Conclusion: Betulin attenuates atherosclerosis in apoE -/-mice by promoting cholesterol efflux in macrophages.

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Section: Discussionmentioning

confidence: 99%

Betulin attenuates atherosclerosis in apoE−/− mice by up-regulating ABCA1 and ABCG1

et al. 2016

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“…The presence of metallic debris may be attributed to the unintended wear mechanism of impingement between the metallic endplates arising from malpositioning and/or subsidence, which was noted in more than 50% of contemporary fixed-bearing device retrievals in a separate retrieval study [20]. Interestingly, considerable amounts of hemosiderin were present in many of these tissues, indicative of phagocytosis of erythrocytes and degradation of hemoglobin by macrophages [13,32]. The exact contribution of hemosiderin to revision remains unclear; however, a previous study has associated the deposition with the accumulation of activated macrophages that are positive for osteoclastic cell markers [25].…”

Section: Discussionmentioning

confidence: 99%

UHMWPE Wear Debris and Tissue Reactions Are Reduced for Contemporary Designs of Lumbar Total Disc Replacements

Veruva

Lanman

Isaza

et al. 2015

Clinical Orthopaedics &Amp; Related Research

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Background Lumbar total disc replacement (L-TDR) is a procedure used to relieve back pain and maintain mobility. Contemporary metal-on-polyethylene (MoP) L-TDRs were developed to address wear performance concerns about historical designs, but wear debris generation and periprosthetic tissue reactions for these newer implants have not been determined. Questions/purposes The purpose of this study was to determine (1) whether periprosthetic ultrahigh-molecularweight polyethylene (UHMWPE) wear debris and biological responses were present in tissues from revised contemporary MoP L-TDRs that contain conventional cores fabricated from c-inert-sterilized UHMWPE; (2) how fixed-versus mobile-bearing design affected UHMWPE wear particle number, shape, and size; and (3) how these wear particle characteristics compare with historical MoP L-TDRs that contain cores fabricated from c-air-sterilized UHMWPE. Methods We evaluated periprosthetic tissues from 11 patients who received eight fixed-bearing ProDisc-L and four mobile-bearing CHARITÉ contemporary L-TDRs with a mean implantation time of 4.1 and 2.7 years, respectively. Histologic analysis of tissues was performed to assess biological responses and polarized light microscopy was used to quantify number and size/shape characteristics of UHMWPE wear particles from the fixed-and mobile-bearing devices. Comparisons were made to previously reported particle data for historical L-TDRs. Results Five of seven (71%) fixed-bearing and one of four mobile-bearing L-TDR patient tissues contained at least 4 particles/mm 2 wear with associated macrophage infiltration. Tissues with wear debris were highly vascularized, whereas those without debris were more necrotic. Given the samples available, the tissue around mobile-bearing L-TDR was observed to contain 87% more, 11% rounder, and 11% lesselongated wear debris compared with tissues around fixedbearing devices; however, there were no significant differences. Compared with historical L-TDRs, UHMWPE particle number and circularity for contemporary L-TDRs were 99% less (p = 0.003) and 50% rounder (p = 0.003). Conclusions In this preliminary study, short-term results suggest there was no significant influence of fixed-or mobile-bearing designs on wear particle characteristics of contemporary L-TDRs, but conventional UHMWPE has notably improved the wear resistance of these devices compared with historical UHMWPE.

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“…However, it has been shown that phagocytosis of apoptotic cells by lipid-loaded macrophages is severely impaired in advanced atherosclerotic lesions, resulting in accumulation of proinflammatory necrotic debris and plaque instability (23,24). Moreover, the intracellular autophagy pathway in lipid-loaded macrophages has also been shown to be impaired (25). Thus, a better understanding of how apoptosis and autophagy are being regulated in vascular lesion cells is essential.…”

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confidence: 99%

Apolipoprotein L6, Induced in Atherosclerotic Lesions, Promotes Apoptosis and Blocks Beclin 1-dependent Autophagy in Atherosclerotic Cells

Zhaorigetu

Yang

Toma

et al. 2011

Journal of Biological Chemistry

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Inflammatory cytokine-regulated apoptosis and autophagy play pivotal roles in plaque rupture and thrombosis of atherosclerotic lesions. However, the molecular interplay between apoptosis and autophagy in vascular cells has not been investigated. Our prior study showed that human apolipoprotein L6 (ApoL6), a pro-apoptotic BH3-only member of the Bcl-2 family, was one of the downstream targets of interferon-␥ (INF␥), which sensitizes atherosclerotic lesion-derived cells (LDCs) to Fas-induced apoptosis. To investigate whether ApoL6 plays a causal role in atherosclerotic apoptosis and autophagy, in this study, we demonstrate that IFN␥ treatment itself strongly induces ApoL6, and ApoL6 is highly expressed and partially colocalized with activated caspase 3 in activated smooth muscle cells in atherosclerotic lesions. In addition, overexpression of ApoL6 promotes reactive oxygen species (ROS) generation, caspase activation, and subsequent apoptosis, which can be blocked by pan caspase inhibitor and ROS scavenger. Knockdown of ApoL6 expression by siApoL6 suppresses INF␥-and Fas-mediated apoptosis. Further, ApoL6 binds Bcl-X L , one of the most abundant anti-death proteins in LDCs. Interestingly, forced ApoL6 expression in LDCs induces degradation of Beclin 1, accumulation of p62, and subsequent attenuation of LC3-II formation and translocation and thus autophagy, whereas siApoL6 treatment reverts the phenotype. Taken together, our results suggest that ApoL6 regulates both apoptosis and autophagy in SMCs. IFN␥-initiated, ApoL6-induced apoptosis in vascular cells may be an important factor causing plaque instability and a potential therapeutic target for treating atherosclerosis and cardiovascular disease.Atherosclerosis, a chronic inflammatory disease and the principal cause of heart attack and stroke, contributes to at least 30% of all mortality in the United States (1, 2). The atherosclerotic lesion results from a dynamic interplay involving many elements of dysfunctional wound repair, including proliferation, matrix synthesis, autophagy (self-eating), and apoptosis, in response to insult of the vascular endothelial cells (ECs) 2 and smooth muscle cells (SMCs) of the artery wall (3, 4). The crosstalk between cytokines, chemokines, growth factors, oxidized lipid species/low density lipoproteins (LDLs), and reactive oxygen species (ROS) in atherosclerotic lesions determine cell survival and death (5, 6). Inflammation, based on the particular cellular context, can modulate proliferation or apoptosis (type I programmed cell death) of different cell-types, such as ECs, SMCs, and the inflammatory infiltrate (lymphocytes, and monocytes/macrophages) in atherosclerotic lesions (7,8). With regard to cell death, it has been well documented that during the early stages of lesion development, apoptosis of macrophages contributes to the accumulation of extracellular LDLs and protein debris, while in the later stages, activated SMCs encapsulate the lipid-rich regions, and their persistence contributes to collagen synthesis, matrix accu...

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Phagocytosis in atherosclerosis: Molecular mechanisms and implications for plaque progression and stability

Cited by 244 publications

References 90 publications

Betulin attenuates atherosclerosis in apoE−/− mice by up-regulating ABCA1 and ABCG1

Betulin attenuates atherosclerosis in apoE−/− mice by up-regulating ABCA1 and ABCG1

UHMWPE Wear Debris and Tissue Reactions Are Reduced for Contemporary Designs of Lumbar Total Disc Replacements

Apolipoprotein L6, Induced in Atherosclerotic Lesions, Promotes Apoptosis and Blocks Beclin 1-dependent Autophagy in Atherosclerotic Cells

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