Abstract
Nox4-based NADPH oxidase is a major reactive oxygen species-generating enzyme in the vasculature, but its role in atherosclerosis remains controversial. Objective Our goal was to investigate the mechanisms of endothelial Nox4 in regulating atherosclerosis. Approach and results Atherosclerosis-prone conditions (disturbed blood flow, type I diabetes, and Western diet) downregulated endothelial Nox4 mRNA in arteries. To address whether the downregulated endothelial Nox4 was directly involved in the development of atherosclerosis, we generated mice carrying a human Nox4 P437H dominant negative mutation (Nox4DN), driven by the endothelial specific promoter Tie-2, on atherosclerosis-prone genetic background (ApoE deficient mice) to mimic the effect of decreased endothelial Nox4. Nox4DN significantly increased type I diabetes-induced aortic stiffness and atherosclerotic lesions. Gene analysis indicated that soluble epoxide hydrolase 2 (sEH) was significantly upregulated in Nox4DN endothelial cells (EC). Inhibition of sEH activity in Nox4DN EC suppressed inflammation and macrophage adhesion to EC. On the contrary, overexpression of endothelial wild type Nox4 suppressed sEH, ameliorated Western diet-induced atherosclerosis and decreased aortic stiffness. Conclusions Atherosclerosis-prone conditions downregulated endothelial Nox4 to accelerate the progress of atherosclerosis, at least in part, by upregulating sEH to enhance inflammation.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1382-1391 |
| Number of pages | 10 |
| Journal | Biochimica et Biophysica Acta - Molecular Basis of Disease |
| Volume | 1863 |
| Issue number | 6 |
| DOIs | |
| State | Published - Jun 1 2017 |
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Keywords
- Atherosclerosis
- Endothelium
- Nox4
- Soluble epoxide hydrolase 2
- Type I diabetes
ASJC Scopus subject areas
- Molecular Medicine
- Molecular Biology
Cite this
Endothelial Nox4-based NADPH oxidase regulates atherosclerosis via soluble epoxide hydrolase. / Hu, Pingping; Wu, Xiaojuan; Khandelwal, Alok R.; Yu, Weimin; Xu, Zaicheng; Chen, Lili; Yang, Jian; Weisbrod, Robert M.; Lee, Kin Sing Stephen; Seta, Francesca; Hammock, Bruce D.; Cohen, Richard A.; Zeng, Chunyu; Tong, Xiaoyong.
In: Biochimica et Biophysica Acta - Molecular Basis of Disease, Vol. 1863, No. 6, 01.06.2017, p. 1382-1391.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Endothelial Nox4-based NADPH oxidase regulates atherosclerosis via soluble epoxide hydrolase
AU - Hu, Pingping
AU - Wu, Xiaojuan
AU - Khandelwal, Alok R.
AU - Yu, Weimin
AU - Xu, Zaicheng
AU - Chen, Lili
AU - Yang, Jian
AU - Weisbrod, Robert M.
AU - Lee, Kin Sing Stephen
AU - Seta, Francesca
AU - Hammock, Bruce D.
AU - Cohen, Richard A.
AU - Zeng, Chunyu
AU - Tong, Xiaoyong
PY - 2017/6/1
Y1 - 2017/6/1
N2 - Nox4-based NADPH oxidase is a major reactive oxygen species-generating enzyme in the vasculature, but its role in atherosclerosis remains controversial. Objective Our goal was to investigate the mechanisms of endothelial Nox4 in regulating atherosclerosis. Approach and results Atherosclerosis-prone conditions (disturbed blood flow, type I diabetes, and Western diet) downregulated endothelial Nox4 mRNA in arteries. To address whether the downregulated endothelial Nox4 was directly involved in the development of atherosclerosis, we generated mice carrying a human Nox4 P437H dominant negative mutation (Nox4DN), driven by the endothelial specific promoter Tie-2, on atherosclerosis-prone genetic background (ApoE deficient mice) to mimic the effect of decreased endothelial Nox4. Nox4DN significantly increased type I diabetes-induced aortic stiffness and atherosclerotic lesions. Gene analysis indicated that soluble epoxide hydrolase 2 (sEH) was significantly upregulated in Nox4DN endothelial cells (EC). Inhibition of sEH activity in Nox4DN EC suppressed inflammation and macrophage adhesion to EC. On the contrary, overexpression of endothelial wild type Nox4 suppressed sEH, ameliorated Western diet-induced atherosclerosis and decreased aortic stiffness. Conclusions Atherosclerosis-prone conditions downregulated endothelial Nox4 to accelerate the progress of atherosclerosis, at least in part, by upregulating sEH to enhance inflammation.
AB - Nox4-based NADPH oxidase is a major reactive oxygen species-generating enzyme in the vasculature, but its role in atherosclerosis remains controversial. Objective Our goal was to investigate the mechanisms of endothelial Nox4 in regulating atherosclerosis. Approach and results Atherosclerosis-prone conditions (disturbed blood flow, type I diabetes, and Western diet) downregulated endothelial Nox4 mRNA in arteries. To address whether the downregulated endothelial Nox4 was directly involved in the development of atherosclerosis, we generated mice carrying a human Nox4 P437H dominant negative mutation (Nox4DN), driven by the endothelial specific promoter Tie-2, on atherosclerosis-prone genetic background (ApoE deficient mice) to mimic the effect of decreased endothelial Nox4. Nox4DN significantly increased type I diabetes-induced aortic stiffness and atherosclerotic lesions. Gene analysis indicated that soluble epoxide hydrolase 2 (sEH) was significantly upregulated in Nox4DN endothelial cells (EC). Inhibition of sEH activity in Nox4DN EC suppressed inflammation and macrophage adhesion to EC. On the contrary, overexpression of endothelial wild type Nox4 suppressed sEH, ameliorated Western diet-induced atherosclerosis and decreased aortic stiffness. Conclusions Atherosclerosis-prone conditions downregulated endothelial Nox4 to accelerate the progress of atherosclerosis, at least in part, by upregulating sEH to enhance inflammation.
KW - Atherosclerosis
KW - Endothelium
KW - Nox4
KW - Soluble epoxide hydrolase 2
KW - Type I diabetes
UR - http://www.scopus.com/inward/record.url?scp=85018268587&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85018268587&partnerID=8YFLogxK
U2 - 10.1016/j.bbadis.2017.02.004
DO - 10.1016/j.bbadis.2017.02.004
M3 - Article
AN - SCOPUS:85018268587
VL - 1863
SP - 1382
EP - 1391
JO - Biochimica et Biophysica Acta - Molecular Basis of Disease
JF - Biochimica et Biophysica Acta - Molecular Basis of Disease
SN - 0925-4439
IS - 6
ER -