Sterol Regulatory Element Binding Protein 2 Activation of NLRP3 Inflammasome in Endothelium Mediates Hemodynamic-Induced Atherosclerosis Susceptibility

Han Xiao, Min Lu, Ting Yang Lin, Zhen Chen, Gang Chen, Wei-Chi Wang, Traci Marin, Tzu-pin Shentu, Liang Wen, Brendan Gongol, Wei Sun, Xiao Liang, Ju Chen, Hsien-Da Huang, Joao H. F. Pedra, David A. Johnson, Shyy John Y. -J.

Research output: Contribution to journalArticlepeer-review

150 Scopus citations

Abstract

Background-The molecular basis for the focal nature of atherosclerotic lesions is poorly understood. Here, we explored whether disturbed flow patterns activate an innate immune response to form the NLRP3 inflammasome scaffold in vascular endothelial cells via sterol regulatory element binding protein 2 (SREBP2).

Methods and Results-Oscillatory flow activates SREBP2 and induces NLRP3 inflammasome in endothelial cells. The underlying mechanisms involve SREBP2 transactivating NADPH oxidase 2 and NLRP3. Consistently, SREBP2, NADPH oxidase 2, and NLRP3 levels were elevated in atheroprone areas of mouse aortas, suggesting that the SREBP2-activated NLRP3 inflammasome causes functionally disturbed endothelium with increased inflammation. Mimicking the effect of atheroprone flow, endothelial cell-specific overexpression of the activated form of SREBP2 synergized with hyperlipidemia to increase atherosclerosis in the atheroresistant areas of mouse aortas.

Conclusions-Atheroprone flow induces NLRP3 inflammasome in endothelium through SREBP2 activation. This increased innate immunity in endothelium synergizes with hyperlipidemia to cause topographical distribution of atherosclerotic lesions.
Original languageEnglish
Pages (from-to)632-642
Number of pages11
JournalCirculation
Volume128
Issue number6
DOIs
StatePublished - 16 Aug 2013

Keywords

  • atherosclerosis; endothelial cell; NLRP3 protein; human; shear stress; sterol regulatory element binding proteins KeyWords Plus:CHRONIC GRANULOMATOUS-DISEASE; SHEAR-STRESS; CHOLESTEROL HOMEOSTASIS; RECEPTOR ANTAGONIST; HEART-DISEASE; UP-REGULATION; CELLS; MICE; INTERLEUKIN-1-BETA; REGIONS

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