Oxidative stress activates endothelial innate immunity via sterol regulatory element binding protein 2 (SREBP2) transactivation of MicroRNA-92a

Zhen Chen, Liang Wen, Marcy Martin, Chien Yi Hsu, Longhou Fang, Feng Mao Lin, Ting Yang Lin, McKenna J. Geary, Greg G. Geary, Yongli Zhao, David A. Johnson, Jaw Wen Chen, Shing Jong Lin, Shu Chien, Hsien Da Huang, Yury I. Miller, Po Hsun Huang, John Y.J. Shyy

Research output: Contribution to journalArticle

68 Citations (Scopus)

Abstract

Background - Oxidative stress activates endothelial innate immunity and disrupts endothelial functions, including endothelial nitric oxide synthase - derived nitric oxide 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 challenged by diverse oxidative stresses, hypercholesterolemic zebrafish, and angiotensin 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, and Krüppel-like factor 4, leading to NOD-like receptor family pyrin domain-containing 3 inflammasome activation and endothelial nitric oxide synthase inhibition. In endothelial cell - specific SREBP2 transgenic mice, locked nucleic acid - modified antisense miR-92a attenuates inflammasome, improves vasodilation, and ameliorates angiotensin II - induced and aging-related atherogenesis. In patients with coronary artery disease, the level of circulating miR-92a is inversely correlated with endothelial cell - dependent, flow-mediated vasodilation and is positively correlated with serum level of interleukin-1β. Conclusions - Our findings suggest that SREBP2 - miR-92a - inflammasome exacerbates endothelial dysfunction during oxidative stress. Identification of this mechanism may help in the diagnosis or treatment of disorders associated with oxidative stress, innate immune activation, and endothelial dysfunction.

Original languageEnglish
Pages (from-to)805-814
Number of pages10
JournalCirculation
Volume131
Issue number9
DOIs
Publication statusPublished - Jan 1 2015
Externally publishedYes

Fingerprint

Sterol Regulatory Element Binding Protein 2
MicroRNAs
Innate Immunity
Transcriptional Activation
Oxidative Stress
Inflammasomes
Endothelial Cells
Nitric Oxide Synthase Type III
Vasodilation
Angiotensin II
Sirtuin 1
Zebrafish
Interleukin-1
Transgenic Mice
Biological Availability
Endothelium
Coronary Artery Disease
Cultured Cells
Atherosclerosis
Nitric Oxide

Keywords

  • Endothelium
  • Inflammasomes
  • MicroRNA-92
  • Oxidative stress
  • Sterol regulatory element binding protein 2

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Oxidative stress activates endothelial innate immunity via sterol regulatory element binding protein 2 (SREBP2) transactivation of MicroRNA-92a. / Chen, Zhen; Wen, Liang; Martin, Marcy; Hsu, Chien Yi; Fang, Longhou; Lin, Feng Mao; Lin, Ting Yang; Geary, McKenna J.; Geary, Greg G.; Zhao, Yongli; Johnson, David A.; Chen, Jaw Wen; Lin, Shing Jong; Chien, Shu; Huang, Hsien Da; Miller, Yury I.; Huang, Po Hsun; Shyy, John Y.J.

In: Circulation, Vol. 131, No. 9, 01.01.2015, p. 805-814.

Research output: Contribution to journalArticle

Chen, Z, Wen, L, Martin, M, Hsu, CY, Fang, L, Lin, FM, Lin, TY, Geary, MJ, Geary, GG, Zhao, Y, Johnson, DA, Chen, JW, Lin, SJ, Chien, S, Huang, HD, Miller, YI, Huang, PH & Shyy, JYJ 2015, 'Oxidative stress activates endothelial innate immunity via sterol regulatory element binding protein 2 (SREBP2) transactivation of MicroRNA-92a', Circulation, vol. 131, no. 9, pp. 805-814. https://doi.org/10.1161/CIRCULATIONAHA.114.013675
Chen, Zhen ; Wen, Liang ; Martin, Marcy ; Hsu, Chien Yi ; Fang, Longhou ; Lin, Feng Mao ; Lin, Ting Yang ; Geary, McKenna J. ; Geary, Greg G. ; Zhao, Yongli ; Johnson, David A. ; Chen, Jaw Wen ; Lin, Shing Jong ; Chien, Shu ; Huang, Hsien Da ; Miller, Yury I. ; Huang, Po Hsun ; Shyy, John Y.J. / Oxidative stress activates endothelial innate immunity via sterol regulatory element binding protein 2 (SREBP2) transactivation of MicroRNA-92a. In: Circulation. 2015 ; Vol. 131, No. 9. pp. 805-814.
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T1 - Oxidative stress activates endothelial innate immunity via sterol regulatory element binding protein 2 (SREBP2) transactivation of MicroRNA-92a

AU - Chen, Zhen

AU - Wen, Liang

AU - Martin, Marcy

AU - Hsu, Chien Yi

AU - Fang, Longhou

AU - Lin, Feng Mao

AU - Lin, Ting Yang

AU - Geary, McKenna J.

AU - Geary, Greg G.

AU - Zhao, Yongli

AU - Johnson, David A.

AU - Chen, Jaw Wen

AU - Lin, Shing Jong

AU - Chien, Shu

AU - Huang, Hsien Da

AU - Miller, Yury I.

AU - Huang, Po Hsun

AU - Shyy, John Y.J.

PY - 2015/1/1

Y1 - 2015/1/1

N2 - Background - Oxidative stress activates endothelial innate immunity and disrupts endothelial functions, including endothelial nitric oxide synthase - derived nitric oxide 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 challenged by diverse oxidative stresses, hypercholesterolemic zebrafish, and angiotensin 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, and Krüppel-like factor 4, leading to NOD-like receptor family pyrin domain-containing 3 inflammasome activation and endothelial nitric oxide synthase inhibition. In endothelial cell - specific SREBP2 transgenic mice, locked nucleic acid - modified antisense miR-92a attenuates inflammasome, improves vasodilation, and ameliorates angiotensin II - induced and aging-related atherogenesis. In patients with coronary artery disease, the level of circulating miR-92a is inversely correlated with endothelial cell - dependent, flow-mediated vasodilation and is positively correlated with serum level of interleukin-1β. Conclusions - Our findings suggest that SREBP2 - miR-92a - inflammasome exacerbates endothelial dysfunction during oxidative stress. Identification of this mechanism may help in the diagnosis or treatment of disorders associated with oxidative stress, innate immune activation, and endothelial dysfunction.

AB - Background - Oxidative stress activates endothelial innate immunity and disrupts endothelial functions, including endothelial nitric oxide synthase - derived nitric oxide 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 challenged by diverse oxidative stresses, hypercholesterolemic zebrafish, and angiotensin 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, and Krüppel-like factor 4, leading to NOD-like receptor family pyrin domain-containing 3 inflammasome activation and endothelial nitric oxide synthase inhibition. In endothelial cell - specific SREBP2 transgenic mice, locked nucleic acid - modified antisense miR-92a attenuates inflammasome, improves vasodilation, and ameliorates angiotensin II - induced and aging-related atherogenesis. In patients with coronary artery disease, the level of circulating miR-92a is inversely correlated with endothelial cell - dependent, flow-mediated vasodilation and is positively correlated with serum level of interleukin-1β. Conclusions - Our findings suggest that SREBP2 - miR-92a - inflammasome exacerbates endothelial dysfunction during oxidative stress. Identification of this mechanism may help in the diagnosis or treatment of disorders associated with oxidative stress, innate immune activation, and endothelial dysfunction.

KW - Endothelium

KW - Inflammasomes

KW - MicroRNA-92

KW - Oxidative stress

KW - Sterol regulatory element binding protein 2

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