Novel anti-inflammatory strategies in atherosclerosis

Valk, Fleur M. van der; Wijk, Diederik F. van; Stroes, Erik S.G.

doi:10.1097/mol.0b013e3283587543

Cited by 43 publications

(19 citation statements)

References 92 publications

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“…MCP-1 and its receptor CCR2, as well as CX3CL1 and its receptor CX3CR1, were reduced in the atorvastatin-treated group. CCR2 is expressed on the majority of blood monocytes, other leukocytes, and a subset of T cells, mainly responding to directed cell migration toward its primary ligand MCP1 [18]. In addition, CCR2-deficient animals ex decreased susceptibility to atherosclerosis and decreased intimal hyperplasia following arterial injury [19]–[20].…”

Section: Discussionmentioning

confidence: 99%

Atorvastatin Improves Plaque Stability in ApoE-Knockout Mice by Regulating Chemokines and Chemokine Receptors

Nie

et al. 2014

PLoS ONE

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It is well documented that statins protect atherosclerotic patients from inflammatory changes and plaque instability in coronary arteries. However, the underlying mechanisms are not fully understood. Using a previously established mouse model for vulnerable atherosclerotic plaque, we investigated the effect of atorvastatin (10 mg/kg/day) on plaque morphology. Atorvastatin did not lower plasma total cholesterol levels or affect plaque progression at this dosage; however, vulnerable plaque numbers were significantly reduced in the atorvastatin-treated group compared to control. Detailed examinations revealed that atorvastatin significantly decreased macrophage infiltration and subendothelial lipid deposition, reduced intimal collagen content, and elevated collagenase activity and expression of matrix metalloproteinases (MMPs). Because vascular inflammation is largely driven by changes in monocyte/macrophage numbers in the vessel wall, we speculated that the anti-inflammatory effect of atorvastatin may partially result from decreased monocyte recruitment to the endothelium. Further experiments showed that atorvastatin downregulated expression of the chemokines monocyte chemoattractant protein (MCP)-1, chemokine (C-X3-C motif) ligand 1 (CX3CL1) and their receptors CCR2 and, CX3CR1, which are mainly responsible for monocyte recruitment. In addition, levels of the plasma inflammatory markers C-reactive protein (CRP) and tumor necrosis factor (TNF)-α were also significantly decrease in atorvastatin-treated mice. Collectively, our results demonstrate that atorvastatin can improve plaque stability in mice independent of plasma cholesterol levels. Given the profound inhibition of macrophage infiltration into atherosclerotic plaques, we propose that statins may partly exert protective effects by modulating levels of chemokines and their receptors. These findings elucidate yet another atheroprotective mechanism of statins.

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Section: Discussionmentioning

confidence: 99%

Atorvastatin Improves Plaque Stability in ApoE-Knockout Mice by Regulating Chemokines and Chemokine Receptors

Nie

et al. 2014

PLoS ONE

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“…9 Reprogramming macrophages toward a M2 phenotype may prevent plaque rupture and promote plaque resolution by encouraging matrix deposition. 19,20 In the case of cancer, tumor-associated macrophages (TAMs) are thought to induce anti-inflammatory signaling that helps protect the tumor from immune assault. 21 Recent evidence suggests presenting M1-activating factors to TAMs can help engage the immune system to attack the tumor.…”

Section: Introductionmentioning

confidence: 99%

Regulation of macrophage polarization and plasticity by complex activation signals

Smith

Tse

Read

et al. 2016

Integrative Biology

142

102

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Macrophages are versatile cells of the immune system that play an important role in both advancing and resolving inflammation. Macrophage activation has been described as a continuum, and different stimuli lead to M1, M2, or mixed phenotypes. In addition, macrophages expressing markers associated with both M1 and M2 function are observed in vivo. Using flow cytometry, we examine how macrophage populations respond to combined M1 and M2 activation signals, presented either simultaneously or sequentially. We demonstrate that macrophages exposed to a combination of LPS, IFN-γ, IL-4, and IL-13 acquire a mixed activation state, with individual cells expressing both M1 marker CD86 and M2 marker CD206 instead of polarizing to discrete phenotypes. Over time, co-stimulated macrophages lose expression of CD86 and display increased expression of CD206. In addition, we find that exposure to LPS/IFN-γ potentiates the subsequent response to IL-4/IL-13, whereas pre-polarization with IL-4/IL-13 inhibits the response to LPS/IFN-γ. Mathematical modeling of candidate regulatory networks indicates that a complex inter-dependence of M1- and M2-associated pathways underlies macrophage activation. Specifically, a mutual inhibition motif was not by itself sufficient to reproduce the temporal marker expression data; incoherent feed-forward of M1 activation as well as both inhibition and activation of M2 by M1 were required. Together these results corroborate a continuum model of macrophage activation and demonstrate that phenotypic markers evolve with time and with exposure to complex signals.

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“…2,3 Although regulation of IL-6 has been suggested as a therapeutic target in atherosclerosis, 4,5 there is a lack of prospective data on the long-term effects of IL-6 on the progression of atherosclerosis. Here, we report the results of a 9-year follow-up study of carotid atherosclerosis in patients with vascular risk factors aimed at elucidating the association between the long-term progression of atherosclerosis and chronic elevation of IL-6 levels.…”

mentioning

confidence: 99%

Association of Interleukin-6 With the Progression of Carotid Atherosclerosis

Okazaki

Sakaguchi

Miwa

et al. 2014

Stroke

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Background and Purpose-Limited information is available on the long-term effects of interleukin-6 (IL-6) on systemic atherosclerosis. The purpose of the present study was to clarify the relationship between chronic elevation of IL-6 and the long-term progression of carotid atherosclerosis. Methods-We prospectively evaluated 210 patients with ≥1 vascular risk factors for 9.0±1.0 years. Carotid mean-maximal intima-media thickness (mmIMT), the serum high-sensitivity C-reactive protein (hs-CRP) level, and the serum IL-6 level were measured at baseline and every 3 years. The associations between the progression of mmIMT and the long-term average levels of hs-CRP and IL-6 were analyzed. Results-Carotid mmIMT increased throughout the study period (0.031±0.026 mm/y). Baseline mmIMT was significantly associated with baseline hs-CRP (P=0.002) and baseline IL-6 (P<0.001) levels. Progression of mmIMT was positively correlated with average hs-CRP (P=0.001) and average IL-6 (P<0.001) levels. When adjusted for age, sex, traditional risk factors, and baseline mmIMT, mmIMT progression remained significantly associated only with the average IL-6 level (standardized β=0.17; P=0.02), but not with the average hs-CRP level (standardized β=0.10; P=0.18). Conclusions-Chronic elevation of serum IL-6 was associated with the progression of atherosclerosis in patients with vascular risk factors. IL-6 could be used as a quantitative marker and a potential therapeutic target for accelerated atherosclerosis. (Stroke. 2014;45:2924-2929.)

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Novel anti-inflammatory strategies in atherosclerosis

Cited by 43 publications

References 92 publications

Atorvastatin Improves Plaque Stability in ApoE-Knockout Mice by Regulating Chemokines and Chemokine Receptors

Atorvastatin Improves Plaque Stability in ApoE-Knockout Mice by Regulating Chemokines and Chemokine Receptors

Regulation of macrophage polarization and plasticity by complex activation signals

Association of Interleukin-6 With the Progression of Carotid Atherosclerosis

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