Targeting IRE1 with small molecules counteracts progression of atherosclerosis
Author(s)
Date
2017-01Source 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
ArticleItem Usage Stats
149
views
views
104
downloads
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
AtherosclerosisEndoplasmic 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/11693/37214Published Version (Please cite this version)
https://doi.org/10.1073/pnas.1621188114Collections
Related items
Showing items related by title, author, creator and subject.
-
TRIB2 confers resistance to anti-cancer therapy by activating the serine/threonine protein kinase AKT
Hill, R.; Madureira, P. A.; Ferreira, B.; Baptista, I.; Machado, S.; Colaço, L.; Dos Santos, M.; Liu, N.; Dopazo, A.; Ugurel, S.; Adrienn, A.; Kiss-Toth, E.; Isbilen, M.; Gure, A. O.; Link, W. (Nature Publishing Group, 2017)Intrinsic and acquired resistance to chemotherapy is the fundamental reason for treatment failure for many cancer patients. The identification of molecular mechanisms involved in drug resistance or sensitization is imperative. ... -
Mutation in TOR1AIP1 encoding LAP1B in a form of muscular dystrophy: A novel gene related to nuclear envelopathies
Kayman-Kurekci G.; Talim, B.; Korkusuz P.; Sayar, N.; Sarioglu, T.; Oncel I.; Sharafi P.; Gundesli H.; Balci-Hayta, B.; Purali, N.; Serdaroglu-Oflazer P.; Topaloglu H.; Dincer P. (Elsevier Ltd, 2014)We performed genome-wide homozygosity mapping and mapped a novel myopathic phenotype to chromosomal region 1q25 in a consanguineous family with three affected individuals manifesting proximal and distal weakness and atrophy, ... -
GOPred: GO molecular function prediction by combined classifiers
Saraç Ö.S.; Atalay V.; Cetin-Atalay, R. (2010)Functional protein annotation is an important matter for in vivo and in silico biology. Several computational methods have been proposed that make use of a wide range of features such as motifs, domains, homology, structure ...