Resolvin E1 attenuates atherosclerosis in absence of cholesterol-lowering effects and on top of atorvastatin

Salic, Kanita; Morrison, Martine C.; Verschuren, Lars; Wielinga, Peter Y.; Wu, Lijun; Kleemann, Robert; Gjörstrup, P.; Kooistra, Teake

doi:10.1016/j.atherosclerosis.2016.05.001

Cited by 93 publications

(63 citation statements)

References 41 publications

(57 reference statements)

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“…In summary, we have demonstrated that RvE1 attenuates neointima formation in response to injury through the suppression of inflammatory reactions and VSMC migration. Given that RvE1 confers multiple protective effects in an atherosclerosis setting (72,73) as well as myocardial recovery from ischemia and reperfusion (24,74), EPA supplementation or RvE1 itself may serve as a viable agent for the future prevention of in-stent restenosis.…”

Section: Discussionmentioning

confidence: 99%

Resolvin E1 attenuates inj ury‐induced vascular neointimal formation by inhibition of inflammatory responses and vascular smooth muscle cell migration

et al. 2018

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Mechanical insults, such as stent implantation, can induce endothelial injury, vascular inflammation, and ultimately lead to vascular neointimal hyperplasia. Resolvin E1 (RvE1), derived from the ω3 fatty acid eicosapentaenoic acid, can facilitate the resolution of inflammation in many settings. We therefore aimed to determine if there was a role for RvE1 in preventing neointimal formation after arterial injury and to understand the underlying mechanisms. Vascular inflammation and neointimal hyperplasia were induced by wire injury in the femoral arteries of mice. Administration of exogenous RvE1 and endogenously generated RvE1 via dietary supplementation with eicosapentaenoic acid and aspirin markedly reduced vascular neointima formation in this model. Mechanistically, RvE1 was found to inhibit vascular neutrophil infiltration, promote macrophage polarization toward an M2-like phenotype, suppress T-cell trafficking by reducing RANTES secretion from vascular smooth muscle cells, and inhibit vascular smooth muscle cell migration. In summary, RvE1 demonstrated a protective role against vascular inflammation and remodeling in response to mechanical injury, suggesting that it may serve as an adjuvant therapeutic agent for percutaneous coronary interventions, such as stent implantation.-Liu, G., Gong, Y., Zhang, R., Piao, L., Li, X., Liu, Q., Yan, S., Shen, Y., Guo, S., Zhu, M., Yin, H., Funk, C. D., Zhang, J., Yu, Y. Resolvin E1 attenuates injury-induced vascular neointimal formation by inhibition of inflammatory responses and vascular smooth muscle cell migration.

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Section: Discussionmentioning

confidence: 99%

Resolvin E1 attenuates inj ury‐induced vascular neointimal formation by inhibition of inflammatory responses and vascular smooth muscle cell migration

et al. 2018

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“…As expected, CCR-5 has been reported to be involved in atherosclerosis. Increased monocyte CCR-5 expression is associated with atherosclerosis, and statins therapy has been demonstrated to reduce CCR-5 concentrations (51,52). Furthermore, CCR-5 expression in monocytes has been demonstrated to be important for migration during the development of atherosclerosis (53) and the CCR5 antagonist, maraviroc, has been shown to be effective in limiting plaque progression in different atherosclerosis animal models (54).…”

Section: Discussionmentioning

confidence: 99%

Macrophage-derived foam cells impair endothelial barrier function by inducing endothelial-mesenchymal transition via CCL-4

Yang

Luo

Ren

et al. 2017

International Journal of Molecular Medicine

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Recently, endothelial-mesenchymal transition (EndMT) has been demonstrated to play an important role in the development of atherosclerosis, the molecular mechanisms of which remain unclear. In the present study, scanning electron microscopy directly revealed a widened endothelial space and immunohistofluorescence demonstrated that EndMT was increased in human aorta atherosclerotic plaques. M1 macrophage-derived foam cell (M1-FC) supernatants, but not M2 macrophage-derived foam cell (M2-FC) supernatants, induced EndMT. A protein array and enzyme-linked immunosorbent assay identified that the levels of several cytokines, including C-C motif chemokine ligand 4 (CCL-4) were increased in M1-FC supernatants, in which EndMT was promoted, accompanied by increased endothelial permeability and monocyte adhesion. Furthermore, anti-CCL-4 antibody abolished the effects of M1-FC supernatants on EndMT. At the same time, CCL-4 activated its receptor, C-C motif chemokine receptor-5 (CCR-5), and upregulated transforming growth factor-β (TGF-β) expression. Further experiments revealed that EndMT induced by CCL-4 was reversed by treatment with CCR-5 antagonist and the RNA-mediated knockdown of TGF-β. On the whole, the data of the present study suggest that M1-FCs induce EndMT by upregulating CCL-4, and increase endothelial permeability and monocyte adhesion. These data may help to elucidate the important role of EndMT in the development of atherosclerosis.

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“…19 Similarly, 12/15 lipoxygenase, the enzyme responsible for the synthesis of Lipoxin A4, RvD1, and MaR1 was also shown to be protective toward atherosclerosis, 20 setting the stage for the indication that progression of atherosclerosis may be a consequence of failed resolution. 21 Given the associative evidence for atheroprotective effects of the precursors of resolving lipid mediators, and more recently of Resolvin E1 in ApoE*3Leiden mice, 22 we here hypothesized that atheroprogression may partly be explained by an imbalance of the arterial lipid mediator profile. Therefore, we set to investigate how the balance of these mediators changes during the course of atherosclerosis, aiming at identifying relevant resolution-inducing candidates.…”

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confidence: 99%

Resolving Lipid Mediators Maresin 1 and Resolvin D2 Prevent Atheroprogression in Mice

Viola¹,

Lemnitzer²,

Jansen³

et al. 2016

Circulation Research

190

167

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Rationale: Atheroprogression is a consequence of nonresolved inflammation, and currently a comprehensive overview of the mechanisms preventing resolution is missing. However, in acute inflammation, resolution is known to be orchestrated by a switch from inflammatory to resolving lipid mediators. Therefore, we hypothesized that lesional lipid mediator imbalance favors atheroprogression. Objective: To understand the lipid mediator balance during atheroprogression and to establish an interventional strategy based on the delivery of resolving lipid mediators. Methods and Results: Aortic lipid mediator profiling of aortas from Apoe −/− mice fed a high-fat diet for 4 weeks, 8 weeks, or 4 months revealed an expansion of inflammatory lipid mediators, Leukotriene B4 and Prostaglandin E2, and a concomitant decrease of resolving lipid mediators, Resolvin D2 (RvD2) and Maresin 1 (MaR1), during advanced atherosclerosis. Functionally, aortic Leukotriene B4 and Prostaglandin E2 levels correlated with traits of plaque instability, whereas RvD2 and MaR1 levels correlated with the signs of plaque stability. In a therapeutic context, repetitive RvD2 and MaR1 delivery prevented atheroprogression as characterized by halted expansion of the necrotic core and accumulation of macrophages along with increased fibrous cap thickness and smooth muscle cell numbers. Mechanistically, RvD2 and MaR1 induced a shift in macrophage profile toward a reparative phenotype, which secondarily stimulated collagen synthesis in smooth muscle cells. Conclusions: We present evidence for the imbalance between inflammatory and resolving lipid mediators during atheroprogression. Delivery of RvD2 and MaR1 successfully prevented atheroprogression, suggesting that resolving lipid mediators potentially represent an innovative strategy to resolve arterial inflammation.

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Resolvin E1 attenuates atherosclerosis in absence of cholesterol-lowering effects and on top of atorvastatin

Abstract: RvE1 attenuates atherogenesis both alone and on top of a statin. The local effects of RvE1 are demonstrated by the modulated aortic expression of genes involved in inflammatory and immune responses, without altering plasma cholesterol or circulating SAA.

Cited by 93 publications

References 41 publications

Resolvin E1 attenuates inj ury‐induced vascular neointimal formation by inhibition of inflammatory responses and vascular smooth muscle cell migration

Resolvin E1 attenuates inj ury‐induced vascular neointimal formation by inhibition of inflammatory responses and vascular smooth muscle cell migration

Macrophage-derived foam cells impair endothelial barrier function by inducing endothelial-mesenchymal transition via CCL-4

Resolving Lipid Mediators Maresin 1 and Resolvin D2 Prevent Atheroprogression in Mice

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