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      Targeting IRE1 with small molecules counteracts progression of atherosclerosis

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      Author(s)
      Tufanli, O.
      Akillilar, P. T.
      Acosta-Alvear, D.
      Kocaturk, B.
      Onat, U. I.
      Hamid, S. M.
      Çimen, I.
      Walter, P.
      Weber, C.
      Erbay, E.
      Date
      2017-01
      Source Title
      Proceedings of the National Academy of Sciences of the United States of America
      Print ISSN
      0027-8424
      Publisher
      National Academy of Sciences
      Volume
      114
      Issue
      8
      Pages
      E1395 - E1404
      Language
      English
      Type
      Article
      Item Usage Stats
      149
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      104
      downloads
      Abstract
      Metaflammation, an atypical, metabolically induced, chronic lowgrade 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 ERresident 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.
      Keywords
      Atherosclerosis
      Endoplasmic reticulum stress
      Lipotoxicity
      Metaflammation
      Unfolded protein response
      Apolipoprotein E
      Calgranulin A
      Gelatinase B
      inflammasome
      Interleukin 18
      Interleukin 1beta
      Messenger RNA
      Monocyte chemotactic protein 1
      Protein inhibitor
      Protein IRE1
      Reactive oxygen metabolite
      STF 083010
      Unclassified drug
      X box binding protein 1
      Animal cell
      Animal experiment
      Animal model
      Apoptosis
      Article
      Atherogenesis
      Atherosclerosis
      Atherosclerotic plaque
      Bone marrow derived macrophage
      Controlled study
      Disease course
      Endoplasmic reticulum stress
      Gene expression
      Gene targeting
      Human
      Human cell
      Hyperlipidemia
      Hyperlipoproteinemia type 3
      Immune response
      In vivo study
      Lipid blood level
      Lipotoxicity
      Male
      Mouse
      Mouse model
      Nonhuman
      Priority journal
      RNA sequence
      Steady state
      Th1 cell
      Permalink
      http://hdl.handle.net/11693/37214
      Published Version (Please cite this version)
      https://doi.org/10.1073/pnas.1621188114
      Collections
      • Department of Molecular Biology and Genetics 468
      • Nanotechnology Research Center (NANOTAM) 1063
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