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Resolving Lipid Mediators Maresin 1 and Resolvin D2 Prevent Atheroprogression in Mice
Open accessAbstract
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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“in mice, the advanced atherosclerotic lesions are deficient in pro-resolving lipid mediators37,38.”
From Inflammation and its resolution in atherosclerosis: mediators and therapeutic opportunities (2019) · cites this paper as [38]
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“As summarized in this Review, treatment of Western-diet-fed Ldlr−/− mice with athero-targeted nanoparticles packaged with a pro-resolving peptide derived from annexin A1 (Ac2–26) or with SPMs markedly suppressed the formation of necrotic, thin-capped plaques36,38,99,109,118.”
From Inflammation and its resolution in atherosclerosis: mediators and therapeutic opportunities (2019) · cites this paper as [38]
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Metadata
- Authors
- Viola, J. R., Lemnitzer, P., Jansen, Y., Csaba, G., Winter, C., Neideck, C., Silvestre-Roig, C., Dittmar, G., Döring, Y., Drechsler, M., Weber, C., Zimmer, R., Cenac, N., & Soehnlein, O.
- Affiliations
- Inserm (FR)
- From the Institute for Cardiovascular Prevention (IPEK), LMU Munich, Germany (J.R.V., P.L., Y.J., C.W., C.N., C.S.-R., Y.D., M.D., C.W., O.S.); Department of Pathology, Academic Medical Center (AMC), Amsterdam University, The Netherlands (J.R.V., C.S.-R., M.D., O.S.); Department of Informatics, Institute of Bioinformatics, LMU Munich, Germany (G.C., R.Z.); DZHK, Partner Site Munich Heart Alliance, Germany (C.W., Y.D., M.D., C.W., O.S.); Mass Spectrometry Core Facility, Max-Delbrück Center, Berlin...
- ORCID
- Venue
- Circulation Research
- Published
- 2016-10-14
- Volume
- 119
- Issue
- 9
- Pages
- 1030-1038
- ISSN
- 0009-7330 (ISSN-L)
- 1524-4571
- OpenAlex
- W2510102221
- Cited by
- 226
- References
- 55
- Citations by year
- 2026: 14 · 2025: 12 · 2024: 24 · 2023: 26 · 2022: 33 · 2021: 26 · 2020: 22 · 2019: 24 · 2018: 19 · 2017: 22 · 2016: 3
- FWCI
- 23.67
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Circulation Research (publishedVersion)
- PubMed (publishedVersion)
- MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (acceptedVersion)
- Pure Amsterdam UMC (submittedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Funders
- Deutsche Forschungsgemeinschaft
- Agence Nationale de la Recherche
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek
- Topics
- Health Sciences › Nursing › Nutrition and Dietetics › Fatty Acid Research and Health
- Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Cholesterol and Lipid Metabolism
- Keywords
- maresin 1, resolvin D2, inflammation resolution, lipid mediators, atherosclerosis, plaque stability, leukotriene B4, prostaglandin E2, macrophage polarization, smooth muscle cells, collagen synthesis, high-fat diet, necrotic core
- MeSH terms
- Animals, Cells, Cultured, Docosahexaenoic Acids, Mice, Inbred C57BL, Drug Delivery Systems, Mice, Knockout, Disease Progression, Inflammation Mediators, Atherosclerosis, Lipid Metabolism, Mice, Diet, High-Fat
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