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

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.