S-EPMC5036151 - An imbalance between specialized pro-resolving lipid mediators and pro-inflammatory leukotrienes promotes instability of atherosclerotic plaques. - OmicsDI

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

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.

SUBMITTER: Fredman G

PROVIDER: S-EPMC5036151 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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

Fredman Gabrielle G Hellmann Jason J Proto Jonathan D JD Kuriakose George G Colas Romain A RA Dorweiler Bernhard B Connolly E Sander ES Solomon Robert R Jones David M DM Heyer Eric J EJ Spite Matthew M Tabas Ira I

Nature communications 20160923

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 B<sub>4</sub> (LT ...[more]

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Project description:Diabetes and its associated chronic complications present a healthcare challenge on a global scale. Despite improvements in the management of chronic complications of the micro-/macro-vasculature, their growing prevalence and incidence highlights the scale of the problem. It is currently estimated that diabetes affects 425 million people globally and it is anticipated that this figure will rise by 2025 to 700 million people. The vascular complications of diabetes including diabetes-associated atherosclerosis and kidney disease present a particular challenge. Diabetes is the leading cause of end stage renal disease, reflecting fibrosis leading to organ failure. Moreover, diabetes associated states of inflammation, neo-vascularization, apoptosis and hypercoagulability contribute to also exacerbate atherosclerosis, from the metabolic syndrome to advanced disease, plaque rupture and coronary thrombosis. Current therapeutic interventions focus on regulating blood glucose, glomerular and peripheral hypertension and can at best slow the progression of diabetes complications. Recently advanced knowledge of the pathogenesis underlying diabetes and associated complications revealed common mechanisms, including the inflammatory response, insulin resistance and hyperglycemia. The major role that inflammation plays in many chronic diseases has led to the development of new strategies aiming to promote the restoration of homeostasis through the "resolution of inflammation." These strategies aim to mimic the spontaneous activities of the 'specialized pro-resolving mediators' (SPMs), including endogenous molecules and their synthetic mimetics. This review aims to discuss the effect of SPMs [with particular attention to lipoxins (LXs) and resolvins (Rvs)] on inflammatory responses in a series of experimental models, as well as evidence from human studies, in the context of cardio- and reno-vascular diabetic complications, with a brief mention to diabetic retinopathy (DR). These data collectively support the hypothesis that endogenously generated SPMs or synthetic mimetics of their activities may represent lead molecules in a new discipline, namely the 'resolution pharmacology,' offering hope for new therapeutic strategies to prevent and treat, specifically, diabetes-associated atherosclerosis, nephropathy and retinopathy.

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