An imbalance between specialized pro-resolving lipid mediators and pro-inflammatory leukotrienes promotes instability of atherosclerotic plaques

Gabrielle Fredman,Eric J Heyer,Jonathan D Proto,Matthew Spite,Romain A Colas,E Sander Connolly,George Kuriakose,David M Jones,Jason Hellmann,Robert Solomon,Ira Tabas,Bernhard Dorweiler

doi:10.1038/ncomms12859

Abstract

Chronic unresolved inflammation plays a causal role in the development of advanced atherosclerosis, but the mechanisms that prevent resolution in atherosclerosis remain unclear. Here, we use targeted mass spectrometry to identify specialized pro-resolving lipid mediators (SPM) in histologically-defined stable and vulnerable regions of human carotid atherosclerotic plaques. The levels of SPMs, particularly resolvin D1 (RvD1), and the ratio of SPMs to pro-inflammatory leukotriene B4 (LTB4), are significantly decreased in the vulnerable regions. SPMs are also decreased in advanced plaques of fat-fed Ldlr−/− mice. Administration of RvD1 to these mice during plaque progression restores the RvD1:LTB4 ratio to that of less advanced lesions and promotes plaque stability, including decreased lesional oxidative stress and necrosis, improved lesional efferocytosis, and thicker fibrous caps. These findings provide molecular support for the concept that defective inflammation resolution contributes to the formation of clinically dangerous plaques and offer a mechanistic rationale for SPM therapy to promote plaque stability.

Highlights

Chronic unresolved inflammation plays a causal role in the development of advanced atherosclerosis, but the mechanisms that prevent resolution in atherosclerosis remain unclear
The findings of this study provide critical molecular support to the concept that defective resolution of inflammation contributes to atherosclerosis progression[1,2,13,26], and they offer a new framework to understand how this defect may develop
The finding that advanced plaque progression can be suppressed by ‘normalizing’ resolution:inflammation imbalance during a critical period of plaque transformation adds causative support for the concept and provides a mechanistic underpinning to recent studies showing the benefits of resolving mediator therapy in atherosclerosis[27,28,29,30]

Summary

Introduction

Chronic unresolved inflammation plays a causal role in the development of advanced atherosclerosis, but the mechanisms that prevent resolution in atherosclerosis remain unclear. The subset of atherosclerotic plaques that are most important are those that at risk for precipitating acute atherothrombotic clinical events, including myocardial infarction, unstable angina, sudden cardiac death and stroke[11] These socalled ‘vulnerable’ plaques have distinct features, including heightened inflammation and oxidative stress (OS); prominent areas of necrosis, which are composed of dead cells not efficiently cleared by efferocytosis; and thinning of a protective layer of collagen (‘fibrous cap’) that overlies the areas of necrosis in more stable lesions[2,11,12]. These findings provide critical molecular support for the hypothesis that defective resolution contributes to plaque progression and for the concept that SPM ‘restoration’ therapy could promote plaque stabilization

Methods

Results

Conclusion