Joana R Viola1, Patricia Lemnitzer1, Yvonne Jansen1, Gergely Csaba1, Carla Winter1, Carlos Neideck1, Carlos Silvestre-Roig1, Gunnar Dittmar1, Yvonne Döring1, Maik Drechsler1, Christian Weber1, Ralf Zimmer1, Nicolas Cenac1, Oliver Soehnlein2. 1. 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.). 2. 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.
Abstract
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.
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.
Authors: Brennan D Gerlach; Michael Marinello; Justin Heinz; Nicholas Rymut; Brian E Sansbury; Colin O Riley; Sudeshna Sadhu; Zeinab Hosseini; Yoko Kojima; Dale D Tang; Nicholas J Leeper; Matthew Spite; Margarida Barroso; Katey J Rayner; Gabrielle Fredman Journal: Cell Death Differ Date: 2019-06-20 Impact factor: 15.828
Authors: Kathryn J Moore; Simon Koplev; Edward A Fisher; Ira Tabas; Johan L M Björkegren; Amanda C Doran; Jason C Kovacic Journal: J Am Coll Cardiol Date: 2018-10-30 Impact factor: 24.094