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J Mol Cell Cardiol. 2016 Mar;92:30-40. doi: 10.1016/j.yjmcc.2016.01.020. Epub 2016 Jan 23.

Pro-atherogenic role of smooth muscle Nox4-based NADPH oxidase.

Author information

1
Innovative Drug Research Centre, Chongqing University, Chongqing 401331, China. Electronic address: xiaoyongtong@cqu.edu.cn.
2
Vascular Biology Section, Department of Medicine, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA 02118, USA.
3
Innovative Drug Research Centre, Chongqing University, Chongqing 401331, China.
4
Department of Cardiology, Daping Hospital, Third Military Medical University, Chongqing 400042, China.
5
The Nanjing Han & Zaenker Cancer Institute, OG Pharmaceuticals, Nanjing 210019, China.
6
Department of Cardiovascular Diseases, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China.
7
Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, 812-8581, Japan.
8
Department of Entomology & UCD Comprehensive Cancer Center, University of California-Davis, Davis, CA 95616, USA.
9
Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers New Jersey Medical School, Newark, NJ 07103, USA.

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 role of smooth muscle Nox4 in atherosclerosis.

APPROACH AND RESULTS:

Atherosclerosis-prone conditions (disturbed blood flow and Western diet) increased Nox4 mRNA level in smooth muscle of arteries. To address whether upregulated smooth muscle Nox4 under atherosclerosis-prone conditions was directly involved in the development of atherosclerosis, mice carrying a human Nox4 P437H dominant negative mutation (Nox4DN), specifically in smooth muscle, were generated on a FVB/N ApoE deficient genetic background to counter the effect of increased smooth muscle Nox4. Nox4DN significantly decreased aortic stiffness and atherosclerotic lesions, with no effect on blood pressure. Gene analysis indicated that soluble epoxide hydrolase 2 (sEH) was significantly downregulated in Nox4DN smooth muscle cells (SMC), at both mRNA and protein levels. Downregulation of sEH by siRNA decreased SMC proliferation and migration, and suppressed inflammation and macrophage adhesion to SMC.

CONCLUSIONS:

Downregulation of smooth muscle Nox4 inhibits atherosclerosis by suppressing sEH, which, at least in part, accounts for inhibition of SMC proliferation, migration and inflammation.

KEYWORDS:

Atherosclerosis; Nox4; Smooth muscle; Soluble epoxide hydrolase 2

PMID:
26812119
PMCID:
PMC5008453
[Available on 2017-03-01]
DOI:
10.1016/j.yjmcc.2016.01.020
[Indexed for MEDLINE]
Free PMC Article

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