PUBLICATION
Oxidative Stress Activates Endothelial Innate Immunity via Sterol Regulatory Element Binding Protein 2 (SREBP2) Transactivation of MiRNA-92a
- Authors
- Chen, Z., Wen, L., Martin, M., Hsu, C., Fang, L., Lin, F., Lin, T., Geary, M.J., Geary, G., Zhao, Y., Johnson, D.A., Chen, J., Lin, S., Chien, S., Huang, H., Miller, Y.I., Huang, P., Shyy, J.Y.
- ID
- ZDB-PUB-150101-4
- Date
- 2015
- Source
- Circulation 131(9): 805-14 (Journal)
- Registered Authors
- Fang, Longhou, Miller, Yury
- Keywords
- endothelial cell, endothelial dysfunction, inflammasome, inflammation, microRNA, oxidative stress, sterol regulatory element binding proteins
- MeSH Terms
-
- Aged
- Angiotensin II/toxicity
- Animals
- Coronary Disease/blood
- Coronary Disease/physiopathology
- Endothelial Cells/metabolism
- Endothelium, Vascular/metabolism*
- Female
- Free Radical Scavengers/pharmacology
- Gene Expression Regulation
- Genes, Reporter
- HEK293 Cells
- Human Umbilical Vein Endothelial Cells
- Humans
- Hydrogen Peroxide/toxicity
- Hypercholesterolemia/genetics
- Immunity, Innate/genetics*
- Inflammasomes/metabolism*
- Interleukin-1beta/blood
- Lipoproteins, LDL/toxicity
- Male
- Mice
- Mice, Transgenic
- MicroRNAs/biosynthesis*
- MicroRNAs/genetics
- Middle Aged
- Organometallic Compounds/pharmacology
- Oxidative Stress/genetics*
- Oxidative Stress/immunology
- Recombinant Fusion Proteins/metabolism
- Salicylates/pharmacology
- Sterol Regulatory Element Binding Protein 2/genetics
- Sterol Regulatory Element Binding Protein 2/physiology*
- Transcriptional Activation*
- Zebrafish
- Zebrafish Proteins/physiology
- PubMed
- 25550450 Full text @ Circulation
Citation
Chen, Z., Wen, L., Martin, M., Hsu, C., Fang, L., Lin, F., Lin, T., Geary, M.J., Geary, G., Zhao, Y., Johnson, D.A., Chen, J., Lin, S., Chien, S., Huang, H., Miller, Y.I., Huang, P., Shyy, J.Y. (2015) Oxidative Stress Activates Endothelial Innate Immunity via Sterol Regulatory Element Binding Protein 2 (SREBP2) Transactivation of MiRNA-92a. Circulation. 131(9):805-14.
Abstract
Background -Oxidative stress activates endothelial innate immunity and disrupts endothelial functions, including eNOS-derived NO bioavailability. Here, we postulated that oxidative stress induces sterol regulatory element binding protein 2 (SREBP2) and microRNA-92a (miR-92a), which in turn activate endothelial innate immune response, leading to dysfunctional endothelium.
Methods and results -Using cultured endothelial cells (ECs) challenged by diverse oxidative stresses, hypercholesterolemic zebrafish, and Ang II-infused or aged mice, we demonstrated that SREBP2 transactivation of microRNA-92a (miR-92a) is oxidative stress-inducible. The SREBP2-induced miR-92a targets key molecules in endothelial homeostasis, including Sirtuin 1, Krüppel-like factor 2 (KLF2), and KLF4, leading to NOD-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome activation and eNOS inhibition. In EC-specific SREBP2 transgenic mice, locked nucleic acid (LNA)-modified antisense miR-92a (LNA-92a) attenuates inflammasome, improves vasodilation, and ameliorates Ang II-induced and aging-related atherogenesis. In patients with coronary artery disease, the level of circulating miR-92a is inversely correlated with EC-dependent, flow-mediated vasodilation and is positively correlated with serum level of IL-1β.
Conclusions -Our findings suggest that SREBP2-miR-92a-inflammasome exacerbates endothelial dysfunction during oxidative stress. Identification of this mechanism may help in diagnosis and/or treatment of disorders associated with oxidative stress, innate immune activation, and endothelial dysfunction.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping