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Original Research

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

Joana Viola, Patricia Lemnitzer, Yvonne Jansen, Gergely Csaba, Carla Winter, Carlos Neideck, Carlos Silvestre-Roig, Gunnar Dittmar, Yvonne Döring, Maik Drechsler, Christian Weber, Ralf Zimmer, Nicolas Cenac, Oliver Soehnlein
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https://doi.org/10.1161/CIRCRESAHA.116.309492
Circulation Research. 2016;CIRCRESAHA.116.309492
Originally published August 16, 2016
Joana Viola
Institute for Cardiovascular Prevention, LMU Munich
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Patricia Lemnitzer
Institute for Cardiovascular Prevention, LMU Munich
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Yvonne Jansen
Institute for Cardiovascular Prevention, LMU Munich
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Gergely Csaba
Institute of Bioinformatics, LMU Munich
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Carla Winter
Institute for Cardiovascular Prevention, LMU Munich
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Carlos Neideck
Institute for Cardiovascular Prevention, LMU Munich
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Carlos Silvestre-Roig
Institute for Cardiovascular Prevention, LMU Munich
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Gunnar Dittmar
Berlin Institute of Health, Max-Delbrück Center
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Yvonne Döring
Institute for Cardiovascular Prevention, LMU Munich
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Maik Drechsler
Institute for Cardiovascular Prevention, LMU Munich
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Christian Weber
Institute for Cardiovascular Prevention, LMU Munich
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Ralf Zimmer
Institute of Bioinformatics, LMU Munich
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Nicolas Cenac
Inserm U1022
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Oliver Soehnlein
Institute for Cardiovascular Prevention, LMU Munich
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  • For correspondence: oliver.soehnlein@med.uni-muenchen.de
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Abstract

Rationale: Atheroprogression is a consequence of non-resolved 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 delivery of resolving lipid mediators.

Methods and Results: Aortic lipid mediator profiling of aortas from Apoe-/- mice fed a high fat diet for four weeks, eight weeks, or four months revealed an expansion of inflammatory lipid mediators, Leukotriene B4 (LTB4) and Prostaglandin E2 (PGE2), and a concomitant decrease of resolving lipid mediators, Resolvin D2 (RvD2) and Maresin 1 (MaR1), during advanced atherosclerosis. Functionally, aortic LTB4 and PGE2 levels correlated with traits of plaque instability while RvD2 and MaR1 levels correlated with 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 towards 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.

  • Inflammation resolution
  • atherosclerosis
  • inflammation
  • lipid metabolites
  • Received July 6, 2016.
  • Revision received August 10, 2016.
  • Accepted August 16, 2016.
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    Resolving Lipid Mediators Maresin 1 and Resolvin D2 Prevent Atheroprogression in Mice
    Joana Viola, Patricia Lemnitzer, Yvonne Jansen, Gergely Csaba, Carla Winter, Carlos Neideck, Carlos Silvestre-Roig, Gunnar Dittmar, Yvonne Döring, Maik Drechsler, Christian Weber, Ralf Zimmer, Nicolas Cenac and Oliver Soehnlein
    Circulation Research. 2016;CIRCRESAHA.116.309492, originally published August 16, 2016
    https://doi.org/10.1161/CIRCRESAHA.116.309492

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    Resolving Lipid Mediators Maresin 1 and Resolvin D2 Prevent Atheroprogression in Mice
    Joana Viola, Patricia Lemnitzer, Yvonne Jansen, Gergely Csaba, Carla Winter, Carlos Neideck, Carlos Silvestre-Roig, Gunnar Dittmar, Yvonne Döring, Maik Drechsler, Christian Weber, Ralf Zimmer, Nicolas Cenac and Oliver Soehnlein
    Circulation Research. 2016;CIRCRESAHA.116.309492, originally published August 16, 2016
    https://doi.org/10.1161/CIRCRESAHA.116.309492
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