Targeting IRE1 with small molecules counteracts progression of atherosclerosis

dc.citation.epageE1404en_US
dc.citation.issueNumber8en_US
dc.citation.spageE1395en_US
dc.citation.volumeNumber114en_US
dc.contributor.authorTufanli, O.en_US
dc.contributor.authorAkillilar, P. T.en_US
dc.contributor.authorAcosta-Alvear, D.en_US
dc.contributor.authorKocaturk, B.en_US
dc.contributor.authorOnat, U. I.en_US
dc.contributor.authorHamid, S. M.en_US
dc.contributor.authorÇimen, I.en_US
dc.contributor.authorWalter, P.en_US
dc.contributor.authorWeber, C.en_US
dc.contributor.authorErbay, E.en_US
dc.date.accessioned2018-04-12T11:06:07Z
dc.date.available2018-04-12T11:06:07Z
dc.date.issued2017-01en_US
dc.departmentDepartment of Molecular Biology and Geneticsen_US
dc.departmentNanotechnology Research Center (NANOTAM)en_US
dc.description.abstractMetaflammation, 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.en_US
dc.description.provenanceMade available in DSpace on 2018-04-12T11:06:07Z (GMT). No. of bitstreams: 1 bilkent-research-paper.pdf: 179475 bytes, checksum: ea0bedeb05ac9ccfb983c327e155f0c2 (MD5) Previous issue date: 2017en
dc.identifier.doi10.1073/pnas.1621188114en_US
dc.identifier.issn0027-8424
dc.identifier.urihttp://hdl.handle.net/11693/37214
dc.language.isoEnglishen_US
dc.publisherNational Academy of Sciencesen_US
dc.relation.isversionofhttps://doi.org/10.1073/pnas.1621188114en_US
dc.source.titleProceedings of the National Academy of Sciences of the United States of Americaen_US
dc.subjectAtherosclerosisen_US
dc.subjectEndoplasmic reticulum stressen_US
dc.subjectLipotoxicityen_US
dc.subjectMetaflammationen_US
dc.subjectUnfolded protein responseen_US
dc.subjectApolipoprotein Een_US
dc.subjectCalgranulin Aen_US
dc.subjectGelatinase Ben_US
dc.subjectinflammasomeen_US
dc.subjectInterleukin 18en_US
dc.subjectInterleukin 1betaen_US
dc.subjectMessenger RNAen_US
dc.subjectMonocyte chemotactic protein 1en_US
dc.subjectProtein inhibitoren_US
dc.subjectProtein IRE1en_US
dc.subjectReactive oxygen metaboliteen_US
dc.subjectSTF 083010en_US
dc.subjectUnclassified drugen_US
dc.subjectX box binding protein 1en_US
dc.subjectAnimal cellen_US
dc.subjectAnimal experimenten_US
dc.subjectAnimal modelen_US
dc.subjectApoptosisen_US
dc.subjectArticleen_US
dc.subjectAtherogenesisen_US
dc.subjectAtherosclerosisen_US
dc.subjectAtherosclerotic plaqueen_US
dc.subjectBone marrow derived macrophageen_US
dc.subjectControlled studyen_US
dc.subjectDisease courseen_US
dc.subjectEndoplasmic reticulum stressen_US
dc.subjectGene expressionen_US
dc.subjectGene targetingen_US
dc.subjectHumanen_US
dc.subjectHuman cellen_US
dc.subjectHyperlipidemiaen_US
dc.subjectHyperlipoproteinemia type 3en_US
dc.subjectImmune responseen_US
dc.subjectIn vivo studyen_US
dc.subjectLipid blood levelen_US
dc.subjectLipotoxicityen_US
dc.subjectMaleen_US
dc.subjectMouseen_US
dc.subjectMouse modelen_US
dc.subjectNonhumanen_US
dc.subjectPriority journalen_US
dc.subjectRNA sequenceen_US
dc.subjectSteady stateen_US
dc.subjectTh1 cellen_US
dc.titleTargeting IRE1 with small molecules counteracts progression of atherosclerosisen_US
dc.typeArticleen_US

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