Apoptotic Cell Death and Efferocytosis in Atherosclerosis

Vré, Emily A. Van; Ait‐Oufella, Hafid; Tedgui, Alain; Mallat, Ziad

doi:10.1161/atvbaha.111.224873

Cited by 169 publications

(126 citation statements)

References 79 publications

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“…(596). This principle of early apparent benefit but long-term harm from increased macrophage apoptosis harmonizes a number of apparently contradictory findings (1863).…”

Section: Nachr␣1mentioning

confidence: 75%

“…Certain inhibitory "don't eat me" signals, generally displayed on healthy cells, can strongly block efferocytosis. In advanced plaques there appears to be an over-abundance of efferocytosis signals with many awaiting apoptotic cells, suggesting saturation of efferocytosis mechanisms (1791,1863). Several efferocytosis promoting ligands and receptors, together with subsequent intracellular signaling, are discussed below and are reviewed in TABLE 9 and depicted in FIGURE 17.…”

Section: Macrophage-dependent Resolution Of Inflammation: An Optimal mentioning

confidence: 99%

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Molecular Biology of Atherosclerosis

Hopkins

2013

Physiological Reviews

382

344

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At least 468 individual genes have been manipulated by molecular methods to study their effects on the initiation, promotion, and progression of atherosclerosis. Most clinicians and many investigators, even in related disciplines, find many of these genes and the related pathways entirely foreign. Medical schools generally do not attempt to incorporate the relevant molecular biology into their curriculum. A number of key signaling pathways are highly relevant to atherogenesis and are presented to provide a context for the gene manipulations summarized herein. The pathways include the following: the insulin receptor (and other receptor tyrosine kinases); Ras and MAPK activation; TNF-␣ and related family members leading to activation of NF-B; effects of reactive oxygen species (ROS) on signaling; endothelial adaptations to flow including G protein-coupled receptor (GPCR) and integrin-related signaling; activation of endothelial and other cells by modified lipoproteins; purinergic signaling; control of leukocyte adhesion to endothelium, migration, and further activation; foam cell formation; and macrophage and vascular smooth muscle cell signaling related to proliferation, efferocytosis, and apoptosis. This review is intended primarily as an introduction to these key signaling pathways. They have become the focus of modern atherosclerosis research and will undoubtedly provide a rich resource for future innovation toward intervention and prevention of the number one cause of death in the modern world.

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“…(596). This principle of early apparent benefit but long-term harm from increased macrophage apoptosis harmonizes a number of apparently contradictory findings (1863).…”

Section: Nachr␣1mentioning

confidence: 75%

Section: Macrophage-dependent Resolution Of Inflammation: An Optimal mentioning

confidence: 99%

Molecular Biology of Atherosclerosis

Hopkins

2013

Physiological Reviews

382

344

View full text Add to dashboard Cite

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“…45 In such lesions, adequate efferocytosis is sufficient to protect against atherosclerosis. 46 Apoptotic cells and the phagocytes that engulf them produce antiinflammatory cytokines, such as transforming growth factor-β and interleukin-10, which inhibit the early stages of atherosclerosis development. 46 In the present study, we found that the number of TUNEL-positive cells within the plaques was significantly lower in the MK-treatment group, and the apoptotic cells were estimated to be macrophages.…”

Section: Anti-apoptotic Effect Of Mkmentioning

confidence: 99%

“…46 Apoptotic cells and the phagocytes that engulf them produce antiinflammatory cytokines, such as transforming growth factor-β and interleukin-10, which inhibit the early stages of atherosclerosis development. 46 In the present study, we found that the number of TUNEL-positive cells within the plaques was significantly lower in the MK-treatment group, and the apoptotic cells were estimated to be macrophages. In terms of mRNA levels, the ratio of the pro- the use of MK inhibitors (antisense oligoDNA, siRNA, and RNA aptamer) to prevent atherosclerosis progression.…”

Section: Anti-apoptotic Effect Of Mkmentioning

confidence: 99%

Midkine Promotes Atherosclerotic Plaque Formation Through Its Pro-Inflammatory, Angiogenic and Anti-Apoptotic Functions in Apolipoprotein E-Knockout Mice

Takemoto

Horiba

Harada

et al. 2018

Circ J

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ECs and VSMCs, macrophages produce pro-inflammatory cytokines and also participate in lipid retention and vascular cell remodeling during atherosclerosis. 8 Importantly, reduction of macrophage apoptotic activity promotes the development of atherosclerosis, suggesting that macrophage apoptosis provides a critical self-defense mechanism in suppressing atherosclerosis. 9 Midkine (MK) is a basic, low molecular-weight protein that belongs to the family of growth factors and cytokines. 10-12 MK expression is not only strongly induced during the process of inflammation and repair, but it also promotes cell survival and cell migration. 13 MK is closely associated with cancer progression, the onset of inflammatory diseases, and the repair of injured tissues. 14 Recent C ardiovascular diseases are currently the leading cause of death in the world. 1 The most common cause of cardiovascular diseases is atherosclerosis, 1 a process mediated by chronic inflammation, 2-5 during which the accumulation of inflammatory cells within the arterial wall leads to the local production of chemokines, interleukins, and proteases, contributing to changes in the function of endothelial cells (ECs) and vascular smooth muscle cells (VSMCs). EC dysfunction triggers lipid accumulation and promotes leukocyte invasion into the arterial walls. 6 The aberrant proliferation of VSMCs also promotes atherosclerotic plaque formation, although VSMCs in advanced plaques are entirely beneficial because they can inhibit the rupture of the fibrous cap. Background: A recent study suggested that midkine (MK), a heparin-binding growth factor, is associated with atherosclerosis progression in patients with artery disease. It has previously been reported that MK plays a critical role in neointima formation in a restenosis model, whereas the role of MK in the development of atherosclerosis has not been investigated. The present study assessed the effect of MK administration on the process of atherosclerotic plaque formation in apolipoprotein E-knockout (ApoE −/− ) mice. Methods and Results:Using an osmotic pump, human recombinant MK protein was intraperitoneally administered for 12 weeks in C57BL/6 ApoE −/− (ApoE −/− -MK) and ApoE +/+ mice fed a high-fat diet. Saline was administered to the control groups of ApoE −/− (ApoE −/− -saline) and ApoE +/+ mice. The atherosclerotic lesion areas in longitudinal aortic sections were significantly larger in ApoE −/− -MK mice than in ApoE −/− -saline mice. The aortic mRNA levels of pro-inflammatory and angiogenic factors, and the percentage of macrophages in aortic root lesions, were significantly higher in ApoE −/− -MK mice than in ApoE −/− -saline mice, whereas the percentage of apoptotic cells was significantly lower in ApoE −/− -MK mice than in ApoE −/− -saline mice. Conclusions:The systemic administration of MK in ApoE −/− mice promoted atherosclerotic plaque formation through pro-inflammatory, angiogenic, and anti-apoptotic effects. MK may serve as a potential therapeutic target for the prevention of atherosclerosis ...

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“…Macrophages are incapable of limiting the uptake of lipids and, therefore, largely depend on cholesterol efflux pathways to maintain cellular lipid homeostasis. 39 In early atherogenesis, macrophage apoptosis is associated with reduced atherosclerosis progression 40,41 attributable to effective efferocytosis by neighboring phagocytes, which, in turn, reduces proinflammatory mediators present in the lesion. 42 However, as atherosclerosis progresses, efferocytosis becomes impaired.…”

Section: Cd16mentioning

confidence: 99%