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      Targeting IRE1 with small molecules counteracts progression of atherosclerosis

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          Abstract

          Metaflammation, an atypical, metabolically induced, chronic low-grade inflammation, plays an important role in the development of obesity, diabetes, and atherosclerosis. An important primer for metaflammation is the persistent metabolic overloading of the endoplasmic reticulum (ER), leading to its functional impairment. Activation of the unfolded protein response (UPR), a homeostatic regulatory network that responds to ER stress, is a hallmark of all stages of atherosclerotic plaque formation. The most conserved ER-resident UPR regulator, the kinase/endoribonuclease inositol-requiring enzyme 1 (IRE1), is activated in lipid-laden macrophages that infiltrate the atherosclerotic lesions. Using RNA sequencing in macrophages, we discovered that IRE1 regulates the expression of many proatherogenic genes, including several important cytokines and chemokines. We show that IRE1 inhibitors uncouple lipid-induced ER stress from inflammasome activation in both mouse and human macrophages. In vivo, these IRE1 inhibitors led to a significant decrease in hyperlipidemia-induced IL-1β and IL-18 production, lowered T-helper type-1 immune responses, and reduced atherosclerotic plaque size without altering the plasma lipid profiles in apolipoprotein E-deficient mice. These results show that pharmacologic modulation of IRE1 counteracts metaflammation and alleviates atherosclerosis.

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          Most cited references31

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          Recent advances on the role of cytokines in atherosclerosis.

          Atherosclerosis is a chronic inflammatory disease of the arterial wall driven by innate and adaptive immune responses. Inflammation controls the development and the destabilization of arterial plaque. Cells involved in the atherosclerotic process secrete and are activated by soluble factors, known as cytokines. Important recent advances in the comprehension of the mechanisms of atherosclerosis have provided evidence for a dual role of cytokines: proinflammatory and T helper-1-related cytokines promote the development and progression of the disease, whereas antiinflammatory and regulatory T cell-related cytokines exert clear antiatherogenic activities. This review focuses on recent advances regarding the role of cytokines, with the exception of chemokines, in the development, progression, and complications of atherosclerosis.
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            Is Open Access

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

            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.
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              Reducing endoplasmic reticulum stress through a macrophage lipid chaperone alleviates atherosclerosis

              Macrophages exhibit endoplasmic reticulum (ER) stress when exposed to lipotoxic signals associated with atherosclerosis, although the pathophysiological significance and the underlying mechanisms remain unknown. Here, we demonstrate that mitigation of ER stress with a chemical chaperone results in marked protection against lipotoxic death in macrophages and prevents macrophage fatty acid binding protein-4 (aP2) expression. Utilizing genetic and chemical models, we show that aP2 is the predominant regulator of lipid-induced macrophage ER stress. Lipid chaperone effects are mediated by the production of phospholipids rich in monounsaturated fatty acids and bioactive lipids that render macrophages resistant to lipid-induced ER stress. Furthermore, aP2’s impact on macrophage lipid metabolism and ER stress response is mediated by upregulation of key lipogenic enzymes by the liver X receptor. Our results demonstrate the central role for lipid chaperones in regulating ER homeostasis in macrophages in atherosclerosis and that ER responses can be modified, genetically or chemically, to protect the organism against the deleterious effects of hyperlipidemia.
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                Author and article information

                Journal
                Proceedings of the National Academy of Sciences
                Proc Natl Acad Sci USA
                Proceedings of the National Academy of Sciences
                0027-8424
                1091-6490
                February 21 2017
                February 21 2017
                February 21 2017
                January 30 2017
                : 114
                : 8
                : E1395-E1404
                Article
                10.1073/pnas.1621188114
                5338400
                28137856
                4ff1da59-5152-488d-b315-39194fa9ec2c
                © 2017

                Free to read

                http://www.pnas.org/site/misc/userlicense.xhtml

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