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

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.

MerTK receptor cleavage promotes plaque necrosis and defective resolution in atherosclerosis

“…Defective inflammation resolution can be caused by an imbalance between specialized proresolving mediators (SPMs) and proinflammatory lipid mediators in both human and mouse lesions (20,21). Using liquid chromatography-tandem mass spectrometry to assay a wide range of SPMs and proinflammatory lipid mediators in aortic extracts, we found that the global content of SPMs, including resolvin D2, D5, and E3, was significantly increased in Mertk CR extracts (Supplemental Table 1 and Figure 3D).…”

Monocyte-Macrophages and T Cells in Atherosclerosis

“…In this context, several key features of clinically dangerous advanced plaques are characteristic of impaired resolution, including defective efferocytosis, plaque necrosis, and DAMP-mediated inflammation; thinning of the fibrous cap; and oxidative stress. Moreover, the ratio of resolving:inflammatory lipid mediators is markedly lower in advanced murine and human plaques compared with earlier lesions (Fredman et al, 2016; Viola et al, 2016). The therapeutic potential of enhancing resolution in chronic diseases like atherosclerosis could be substantial in that SPMs, unlike anti-inflammatory drugs, suppress inflammation and promote tissue repair in a manner that is less likely to compromise host defense than drugs directly targeting the inflammatory response (Serhan et al, 2007; Tabas and Glass, 2013) (below).…”

The Ins and Outs of Myeloid Cells in Atherosclerosis

“…Besides inducing macrophage egress, also the phenotype shift from proinflammatory (M1) to proresolving macrophages (M2) by resolving lipid mediators can limit atherosclerosis [61, 62]. Resolving lipid mediators, e.g., maresin 1 or resolvin D2, might be a useful tool to resolve atherosclerosis [61] by encouraging apoptosis or stimulating efferocytic cell clearance without affecting the normal immune response or taking the risk of causing systemic inflammation of atherosclerotic-experienced egressed cells.…”

“…Resolving lipid mediators, e.g., maresin 1 or resolvin D2, might be a useful tool to resolve atherosclerosis [61] by encouraging apoptosis or stimulating efferocytic cell clearance without affecting the normal immune response or taking the risk of causing systemic inflammation of atherosclerotic-experienced egressed cells.…”