TY - JOUR
T1 - Pro-atherogenic role of smooth muscle Nox4-based NADPH oxidase
AU - Tong, Xiaoyong
AU - Khandelwal, Alok R.
AU - Wu, Xiaojuan
AU - Xu, Zaicheng
AU - Yu, Weimin
AU - Chen, Caiyu
AU - Zhao, Wanzhou
AU - Yang, Jian
AU - Qin, Zhexue
AU - Weisbrod, Robert M.
AU - Seta, Francesca
AU - Ago, Tetsuro
AU - Lee, Kin Sing Stephen
AU - Hammock, Bruce D.
AU - Sadoshima, Junichi
AU - Cohen, Richard A.
AU - Zeng, Chunyu
N1 - Funding Information:
The authors thank Dr. Jan. L. Breslow from Rockefeller University for FVB/N ApoE −/− mice and Dr. Ajah Shah for Nox4 antibody. This work was supported by National Natural Science Foundation of China ( 31571172 , Tong X), Fundamental Research Funds for the Central Universities ( 0236015202008 , Tong X), American Diabetes Association award ( 7-09-JF-69 , Tong X), NIH R01 HL031607 (Cohen RA and Tong X), R37 HL104017 , Boston University Medical Center Department of Medicine Evans Center Arterial Stiffness ARC . B.D.H. and K.S.S.L. are partially supported by the NIEHS grant R01 ES002710 , NIEHS Superfund Research Program grant P42 ES004699 and NIH CounterAct U54 NS079202 and K.S.S.L. has been partially supported by the NIH Pathway to Independence Award from NIH/NIEHS ( 1K99ES024806-01 ).
Funding Information:
The authors thank Dr. Jan. L. Breslow from Rockefeller University for FVB/N ApoE-/- mice and Dr. Ajah Shah for Nox4 antibody. This work was supported by National Natural Science Foundation of China (31571172, Tong X), Fundamental Research Funds for the Central Universities (0236015202008, Tong X), American Diabetes Association award (7-09-JF-69, Tong X), NIH R01 HL031607 (Cohen RA and Tong X), R37 HL104017, Boston University Medical Center Department of Medicine Evans Center Arterial Stiffness ARC. B. D. H. and K. S. S. L. are partially supported by the NIEHS grant R01 ES002710, NIEHS Superfund Research Program grant P42 ES004699 and NIH CounterAct U54 NS079202 and K. S. S. L. has been partially supported by the NIH Pathway to Independence Award from NIH/NIEHS (1K99ES024806-01).
Publisher Copyright:
© 2016 Elsevier Ltd.
PY - 2016/3/1
Y1 - 2016/3/1
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 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.
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 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.
UR - http://www.scopus.com/inward/record.url?scp=84961328291&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84961328291&partnerID=8YFLogxK
U2 - 10.1016/j.yjmcc.2016.01.020
DO - 10.1016/j.yjmcc.2016.01.020
M3 - Article
C2 - 26812119
AN - SCOPUS:84961328291
SN - 0022-2828
VL - 92
SP - 30
EP - 40
JO - Journal of Molecular and Cellular Cardiology
JF - Journal of Molecular and Cellular Cardiology
ER -