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Targeting IRE1 with small molecules counteracts progression of atherosclerosis.
Tufanli, Ozlem; Telkoparan Akillilar, Pelin; Acosta-Alvear, Diego; Kocaturk, Begum; Onat, Umut Inci; Hamid, Syed Muhammad; Çimen, Ismail; Walter, Peter; Weber, Christian; Erbay, Ebru.
Afiliación
  • Tufanli O; Department of Molecular Biology and Genetics, Bilkent University, Ankara 06800, Turkey.
  • Telkoparan Akillilar P; National Nanotechnology Center, Bilkent University, Ankara 06800, Turkey.
  • Acosta-Alvear D; Department of Molecular Biology and Genetics, Bilkent University, Ankara 06800, Turkey.
  • Kocaturk B; National Nanotechnology Center, Bilkent University, Ankara 06800, Turkey.
  • Onat UI; Howard Hughes Medical Institute, University of California, San Francisco, CA 94143.
  • Hamid SM; Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94143.
  • Çimen I; Department of Molecular Biology and Genetics, Bilkent University, Ankara 06800, Turkey.
  • Walter P; National Nanotechnology Center, Bilkent University, Ankara 06800, Turkey.
  • Weber C; Department of Molecular Biology and Genetics, Bilkent University, Ankara 06800, Turkey.
  • Erbay E; National Nanotechnology Center, Bilkent University, Ankara 06800, Turkey.
Proc Natl Acad Sci U S A ; 114(8): E1395-E1404, 2017 02 21.
Article en En | MEDLINE | ID: mdl-28137856
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-1ß 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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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas Serina-Treonina Quinasas / Aterosclerosis / Bibliotecas de Moléculas Pequeñas / Proteínas de la Membrana Límite: Animals Idioma: En Revista: Proc Natl Acad Sci U S A Año: 2017 Tipo del documento: Article País de afiliación: Turquía Pais de publicación: Estados Unidos
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas Serina-Treonina Quinasas / Aterosclerosis / Bibliotecas de Moléculas Pequeñas / Proteínas de la Membrana Límite: Animals Idioma: En Revista: Proc Natl Acad Sci U S A Año: 2017 Tipo del documento: Article País de afiliación: Turquía Pais de publicación: Estados Unidos