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Sterol Regulatory Element Binding Protein 2 Activation of NLRP3 Inflammasome in Endothelium Mediates Hemodynamic-Induced Atherosclerosis Susceptibility
Open accessAbstract
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.
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“Xiao et al11 additionally reported that atheroprone flow induces the NLRP3 inflammasome in endothelium through serol regulatory element binding protein 2 activation.”
From Trimethylamine‐N‐Oxide Induces Vascular Inflammation by Activating the NLRP3 Inflammasome Through the SIRT3‐SOD2‐mtROS Signaling Pathway (2017) · cites this paper as [11]
In the citing paper
“This increased innate immunity in endothelium synergizes with hyperlipidemia to cause topographical distribution of atherosclerotic lesions.11”
From Trimethylamine‐N‐Oxide Induces Vascular Inflammation by Activating the NLRP3 Inflammasome Through the SIRT3‐SOD2‐mtROS Signaling Pathway (2017) · cites this paper as [11]
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“Moreover, recent studies have demonstrated that sterol regulatory element binding protein 2 activation of NLRP3 inflammasome in endothelium mediates hemodynamic‐induced AS susceptibility,11”
From Trimethylamine‐N‐Oxide Induces Vascular Inflammation by Activating the NLRP3 Inflammasome Through the SIRT3‐SOD2‐mtROS Signaling Pathway (2017) · cites this paper as [11]
In the citing paper
“These results clearly indicate that the NLRP3 inflammasome plays a key role in the pathogenesis of vascular inflammation, thereby contributing to AS development.”
From Trimethylamine‐N‐Oxide Induces Vascular Inflammation by Activating the NLRP3 Inflammasome Through the SIRT3‐SOD2‐mtROS Signaling Pathway (2017) · cites this paper as [11]
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Metadata
- Authors
- Xiao, H., Lu, M., Lin, T. Y., Chen, Z., Chen, G., Wang, W.-C., Marin, T., Shentu, T.-P., Wen, L., Gongol, B., Sun, W., Liang, X., Chen, J., Huang, H.-D., Pedra, J. H. F., Johnson, D. A., & Shyy, J. Y.-J.
- Affiliations
- University of California, Riverside (US)
- ORCID
- Venue
- Circulation
- Published
- 2013-08-06
- Volume
- 128
- Issue
- 6
- Pages
- 632-642
- ISSN
- 0009-7322 (ISSN-L)
- 1524-4539
- PMC
- PMC3798034
- OpenAlex
- W2022621797
- Cited by
- 257
- References
- 47
- Citations by year
- 2026: 14 · 2025: 15 · 2024: 14 · 2023: 15 · 2022: 22 · 2021: 32 · 2020: 18 · 2019: 23 · 2018: 15 · 2017: 19 · 2016: 25 · 2015: 17 · 2014: 25 · 2013: 2
- FWCI
- 12.71
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Circulation (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Natural Science Foundation of China (81270349)
- National Science Council (NSC 101-2311-B-009-003-MY3, NSC 100-2627-B-009-002, NSC 101-2911-I-009-101)
- National Institutes of Health
- University of California, San Diego
- National Heart, Lung, and Blood Institute (R01HL105318, R01HL089940, HL89940, HL105318)
- National Institute of Allergy and Infectious Diseases (R01AI093653)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Cholesterol and Lipid Metabolism
- Keywords
- SREBP2, NLRP3 inflammasome, endothelial cells, oscillatory flow, flow disturbance, atherosclerosis, hemodynamics, NADPH oxidase 2, innate immunity, hyperlipidemia
- MeSH terms
- NLR Family, Pyrin Domain-Containing 3 Protein, NADPH Oxidase 2, Animals, Apolipoproteins E, Carrier Proteins, Hemodynamics, Humans, Immunity, Innate, Male, Membrane Glycoproteins, Mice, Transgenic, Stress, Mechanical, Vasculitis, NADPH Oxidases, RNA, Small Interfering, MicroRNAs, Endothelial Cells, Atherosclerosis, Mice, Sterol Regulatory Element Binding Protein 2, Inflammasomes, Human Umbilical Vein Endothelial Cells
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