title: Resolving Lipid Mediators Maresin 1 and Resolvin D2 Prevent Atheroprogression in Mice.
abstract: BACKGROUND
  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.
  
  
  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.
authors.affiliation: 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 Institute of Health, Germany (G.D.); and Inserm U1043, CHU Purpan, Toulouse, France (N.C.).
authors.forename: Joana R
authors.initials: JR
authors.lastname: Viola
authors.affiliation: 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 Institute of Health, Germany (G.D.); and Inserm U1043, CHU Purpan, Toulouse, France (N.C.).
authors.forename: Patricia
authors.initials: P
authors.lastname: Lemnitzer
authors.affiliation: 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 Institute of Health, Germany (G.D.); and Inserm U1043, CHU Purpan, Toulouse, France (N.C.).
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Jansen
authors.affiliation: 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 Institute of Health, Germany (G.D.); and Inserm U1043, CHU Purpan, Toulouse, France (N.C.).
authors.forename: Gergely
authors.initials: G
authors.lastname: Csaba
authors.affiliation: 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 Institute of Health, Germany (G.D.); and Inserm U1043, CHU Purpan, Toulouse, France (N.C.).
authors.forename: Carla
authors.initials: C
authors.lastname: Winter
authors.affiliation: 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 Institute of Health, Germany (G.D.); and Inserm U1043, CHU Purpan, Toulouse, France (N.C.).
authors.forename: Carlos
authors.initials: C
authors.lastname: Neideck
authors.affiliation: 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 Institute of Health, Germany (G.D.); and Inserm U1043, CHU Purpan, Toulouse, France (N.C.).
authors.forename: Carlos
authors.initials: C
authors.lastname: Silvestre-Roig
authors.affiliation: 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 Institute of Health, Germany (G.D.); and Inserm U1043, CHU Purpan, Toulouse, France (N.C.).
authors.forename: Gunnar
authors.initials: G
authors.lastname: Dittmar
authors.affiliation: 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 Institute of Health, Germany (G.D.); and Inserm U1043, CHU Purpan, Toulouse, France (N.C.).
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Döring
authors.affiliation: 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 Institute of Health, Germany (G.D.); and Inserm U1043, CHU Purpan, Toulouse, France (N.C.).
authors.forename: Maik
authors.initials: M
authors.lastname: Drechsler
authors.affiliation: 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 Institute of Health, Germany (G.D.); and Inserm U1043, CHU Purpan, Toulouse, France (N.C.).
authors.forename: Christian
authors.initials: C
authors.lastname: Weber
authors.affiliation: 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 Institute of Health, Germany (G.D.); and Inserm U1043, CHU Purpan, Toulouse, France (N.C.).
authors.forename: Ralf
authors.initials: R
authors.lastname: Zimmer
authors.affiliation: 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 Institute of Health, Germany (G.D.); and Inserm U1043, CHU Purpan, Toulouse, France (N.C.).
authors.forename: Nicolas
authors.initials: N
authors.lastname: Cenac
authors.affiliation: 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 Institute of Health, Germany (G.D.); and Inserm U1043, CHU Purpan, Toulouse, France (N.C.). oliver.soehnlein@gmail.com.
authors.forename: Oliver
authors.initials: O
authors.lastname: Soehnlein
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000209:etiology / Q000378:metabolism* / Q000517:prevention & control*; D002478:Cells, Cultured; D059305:Diet, High-Fat / Q000009:adverse effects; D018450:Disease Progression; D004281:Docosahexaenoic Acids / Q000008:administration & dosage / Q000378:metabolism*; D016503:Drug Delivery Systems / Q000379:methods; D018836:Inflammation Mediators / Q000378:metabolism*; D050356:Lipid Metabolism / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout
chemical_list: C535211:7,14-dihydroxydocosa-4,8,10,12,16,19-hexaenoic acid; D018836:Inflammation Mediators; C545423:resolvin D2; D004281:Docosahexaenoic Acids
keywords: atherosclerosis; collagen; high-fat diet; inflammation; macrophages