Pingping Hu1, Xiaojuan Wu1, Alok R Khandelwal2, Weimin Yu1, Zaicheng Xu3, Lili Chen4, Jian Yang3, Robert M Weisbrod2, Kin Sing Stephen Lee5, Francesca Seta2, Bruce D Hammock6, Richard A Cohen2, Chunyu Zeng3, Xiaoyong Tong7. 1. Innovative Drug Research Centre, Chongqing University, Chongqing 401331, China. 2. Vascular Biology Section, Department of Medicine, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA 02118, USA. 3. Department of Cardiology, Daping Hospital, Third Military Medical University, Chongqing 400042, China. 4. Wuhan EasyDiagnosis Biomedicine Co., Ltd., Wuhan 430075, China. 5. Department of Entomology & UCD Comprehensive Cancer Center, University of California-Davis, Davis, CA 95616, USA; Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI 48824, USA. 6. Department of Entomology & UCD Comprehensive Cancer Center, University of California-Davis, Davis, CA 95616, USA. 7. Innovative Drug Research Centre, Chongqing University, Chongqing 401331, China. Electronic address: xiaoyongtong@cqu.edu.cn.
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.
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 humanNox4P437H 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.
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