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Proc Natl Acad Sci U S A. 2017 Feb 21;114(8):E1395-E1404. doi: 10.1073/pnas.1621188114. Epub 2017 Jan 30.

Targeting IRE1 with small molecules counteracts progression of atherosclerosis.

Author information

1
Department of Molecular Biology and Genetics, Bilkent University, Ankara 06800, Turkey.
2
National Nanotechnology Center, Bilkent University, Ankara 06800, Turkey.
3
Howard Hughes Medical Institute, University of California, San Francisco, CA 94143.
4
Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94143.
5
Howard Hughes Medical Institute, University of California, San Francisco, CA 94143; peter@walterlab.ucsf.edu eerbay@bilkent.edu.tr.
6
Institute for Cardiovascular Prevention, Ludwig Maximilian University, Munich 80336, Germany.
7
German Centre for Cardiovascular Research, Munich Heart Alliance, Munich 80336, Germany.
8
Department of Molecular Biology and Genetics, Bilkent University, Ankara 06800, Turkey; peter@walterlab.ucsf.edu eerbay@bilkent.edu.tr.

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.

KEYWORDS:

atherosclerosis; endoplasmic reticulum stress; lipotoxicity; metaflammation; unfolded protein response

PMID:
28137856
PMCID:
PMC5338400
DOI:
10.1073/pnas.1621188114
[Indexed for MEDLINE]
Free PMC Article

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