PMID- 28751569
OWN - NLM
STAT- MEDLINE
DCOM- 20170905
LR  - 20201209
IS  - 1524-4636 (Electronic)
IS  - 1079-5642 (Linking)
VI  - 37
IP  - 9
DP  - 2017 Sep
TI  - CYLD Deubiquitinates Nicotinamide Adenine Dinucleotide Phosphate Oxidase 4 
      Contributing to Adventitial Remodeling.
PG  - 1698-1709
LID - 10.1161/ATVBAHA.117.309859 [doi]
AB  - OBJECTIVE: Transdifferentiation of adventitial fibroblasts (AFs) into 
      myofibroblasts plays a critical role during the vascular remodeling that occurs 
      during atherosclerosis, restenosis, and aortic aneurysm. The 
      ubiquitination/deubiquitination regulatory system is essential for the quality 
      control of proteins. The involvement of ubiquitination/deubiquitination during AF 
      transdifferentiation remains largely unknown. In this study, we determined the 
      role of cylindromatosis (CYLD), a deubiquitinase, in the process of AF 
      differentiation and activation in vitro and in vivo. APPROACH AND RESULTS: 
      Transforming growth factor-beta1 and homocysteine, 2 known inducers of AF 
      transdifferentiation, greatly upregulated CYLD expression in a time- and 
      dose-dependent manner. The silencing of CYLD significantly inhibited AF 
      transdifferentiation and activation as evidenced by the expression of contractile 
      proteins, the production of the proinflammatory cytokines MCP-1 (monocyte 
      chemotactic protein 1) and IL-6 (interleukin-6), the deposition of extracellular 
      matrix, and cell migration. We further asked whether CYLD mediates AF activation 
      via the regulation of nicotinamide adenine dinucleotide phosphate oxidase 4 
      (Nox4) as it is an essential factor during AF transdifferentiation. Indeed, the 
      silencing of CYLD repressed transforming growth factor-beta1-induced and 
      homocysteine-induced Nox4 upregulation and reactive oxygen species production, 
      whereas Nox4 overexpression greatly rescued the inhibitory effect on AF 
      activation by CYLD silencing. Most interestingly, transforming growth factor-beta1 
      and homocysteine repressed Nox4 ubiquitination and prolonged the half-life of 
      Nox4. Moreover, Nox4 was deubiquitinated via a direct interaction with the 
      ubiquitin-specific protease domain of CYLD. In accordance, hyperhomocysteinemia 
      significantly increased adventitial CYLD and Nox4 expression, promoted AF 
      transdifferentiation, and aggravated CaPO(4)-induced abdominal aortic aneurysm in 
      mice. These effects were abolished in CYLD(-/-) mice. CONCLUSIONS: CYLD 
      contributes to the transdifferentiation of AFs via deubiquitinating Nox4 and may 
      play a role in vascular remodeling.
CI  - (c) 2017 American Heart Association, Inc.
FAU - Yu, Bing
AU  - Yu B
AD  - From the Department of Physiology and Pathophysiology, School of Basic Medical 
      Sciences, Peking University, Beijing, P. R. China (B.Y., Z.L., Y.F., Y.W., L.Z., 
      Z.C., F.Y., X.W., W.K.); Key Laboratory of Molecular Cardiovascular Science, 
      Ministry of Education, Beijing, P. R. China (B.Y., Z.L., Y.F., Y.W., L.Z., Z.C., 
      F.Y., X.W., W.K.); and State Key Laboratory of Medicinal Chemical Biology, 
      College of Life Sciences, Nankai University, Tianjin, P. R. China (J.Z.).
FAU - Liu, Ziyi
AU  - Liu Z
AD  - From the Department of Physiology and Pathophysiology, School of Basic Medical 
      Sciences, Peking University, Beijing, P. R. China (B.Y., Z.L., Y.F., Y.W., L.Z., 
      Z.C., F.Y., X.W., W.K.); Key Laboratory of Molecular Cardiovascular Science, 
      Ministry of Education, Beijing, P. R. China (B.Y., Z.L., Y.F., Y.W., L.Z., Z.C., 
      F.Y., X.W., W.K.); and State Key Laboratory of Medicinal Chemical Biology, 
      College of Life Sciences, Nankai University, Tianjin, P. R. China (J.Z.).
FAU - Fu, Yi
AU  - Fu Y
AD  - From the Department of Physiology and Pathophysiology, School of Basic Medical 
      Sciences, Peking University, Beijing, P. R. China (B.Y., Z.L., Y.F., Y.W., L.Z., 
      Z.C., F.Y., X.W., W.K.); Key Laboratory of Molecular Cardiovascular Science, 
      Ministry of Education, Beijing, P. R. China (B.Y., Z.L., Y.F., Y.W., L.Z., Z.C., 
      F.Y., X.W., W.K.); and State Key Laboratory of Medicinal Chemical Biology, 
      College of Life Sciences, Nankai University, Tianjin, P. R. China (J.Z.).
FAU - Wang, Yingbao
AU  - Wang Y
AD  - From the Department of Physiology and Pathophysiology, School of Basic Medical 
      Sciences, Peking University, Beijing, P. R. China (B.Y., Z.L., Y.F., Y.W., L.Z., 
      Z.C., F.Y., X.W., W.K.); Key Laboratory of Molecular Cardiovascular Science, 
      Ministry of Education, Beijing, P. R. China (B.Y., Z.L., Y.F., Y.W., L.Z., Z.C., 
      F.Y., X.W., W.K.); and State Key Laboratory of Medicinal Chemical Biology, 
      College of Life Sciences, Nankai University, Tianjin, P. R. China (J.Z.).
FAU - Zhang, Lu
AU  - Zhang L
AD  - From the Department of Physiology and Pathophysiology, School of Basic Medical 
      Sciences, Peking University, Beijing, P. R. China (B.Y., Z.L., Y.F., Y.W., L.Z., 
      Z.C., F.Y., X.W., W.K.); Key Laboratory of Molecular Cardiovascular Science, 
      Ministry of Education, Beijing, P. R. China (B.Y., Z.L., Y.F., Y.W., L.Z., Z.C., 
      F.Y., X.W., W.K.); and State Key Laboratory of Medicinal Chemical Biology, 
      College of Life Sciences, Nankai University, Tianjin, P. R. China (J.Z.).
FAU - Cai, Zeyu
AU  - Cai Z
AD  - From the Department of Physiology and Pathophysiology, School of Basic Medical 
      Sciences, Peking University, Beijing, P. R. China (B.Y., Z.L., Y.F., Y.W., L.Z., 
      Z.C., F.Y., X.W., W.K.); Key Laboratory of Molecular Cardiovascular Science, 
      Ministry of Education, Beijing, P. R. China (B.Y., Z.L., Y.F., Y.W., L.Z., Z.C., 
      F.Y., X.W., W.K.); and State Key Laboratory of Medicinal Chemical Biology, 
      College of Life Sciences, Nankai University, Tianjin, P. R. China (J.Z.).
FAU - Yu, Fang
AU  - Yu F
AD  - From the Department of Physiology and Pathophysiology, School of Basic Medical 
      Sciences, Peking University, Beijing, P. R. China (B.Y., Z.L., Y.F., Y.W., L.Z., 
      Z.C., F.Y., X.W., W.K.); Key Laboratory of Molecular Cardiovascular Science, 
      Ministry of Education, Beijing, P. R. China (B.Y., Z.L., Y.F., Y.W., L.Z., Z.C., 
      F.Y., X.W., W.K.); and State Key Laboratory of Medicinal Chemical Biology, 
      College of Life Sciences, Nankai University, Tianjin, P. R. China (J.Z.).
FAU - Wang, Xian
AU  - Wang X
AD  - From the Department of Physiology and Pathophysiology, School of Basic Medical 
      Sciences, Peking University, Beijing, P. R. China (B.Y., Z.L., Y.F., Y.W., L.Z., 
      Z.C., F.Y., X.W., W.K.); Key Laboratory of Molecular Cardiovascular Science, 
      Ministry of Education, Beijing, P. R. China (B.Y., Z.L., Y.F., Y.W., L.Z., Z.C., 
      F.Y., X.W., W.K.); and State Key Laboratory of Medicinal Chemical Biology, 
      College of Life Sciences, Nankai University, Tianjin, P. R. China (J.Z.).
FAU - Zhou, Jun
AU  - Zhou J
AD  - From the Department of Physiology and Pathophysiology, School of Basic Medical 
      Sciences, Peking University, Beijing, P. R. China (B.Y., Z.L., Y.F., Y.W., L.Z., 
      Z.C., F.Y., X.W., W.K.); Key Laboratory of Molecular Cardiovascular Science, 
      Ministry of Education, Beijing, P. R. China (B.Y., Z.L., Y.F., Y.W., L.Z., Z.C., 
      F.Y., X.W., W.K.); and State Key Laboratory of Medicinal Chemical Biology, 
      College of Life Sciences, Nankai University, Tianjin, P. R. China (J.Z.). 
      kongw@bjmu.edu.cn Junzhou@nankai.edu.cn.
FAU - Kong, Wei
AU  - Kong W
AD  - From the Department of Physiology and Pathophysiology, School of Basic Medical 
      Sciences, Peking University, Beijing, P. R. China (B.Y., Z.L., Y.F., Y.W., L.Z., 
      Z.C., F.Y., X.W., W.K.); Key Laboratory of Molecular Cardiovascular Science, 
      Ministry of Education, Beijing, P. R. China (B.Y., Z.L., Y.F., Y.W., L.Z., Z.C., 
      F.Y., X.W., W.K.); and State Key Laboratory of Medicinal Chemical Biology, 
      College of Life Sciences, Nankai University, Tianjin, P. R. China (J.Z.). 
      kongw@bjmu.edu.cn Junzhou@nankai.edu.cn.
LA  - eng
PT  - Journal Article
DEP - 20170727
PL  - United States
TA  - Arterioscler Thromb Vasc Biol
JT  - Arteriosclerosis, thrombosis, and vascular biology
JID - 9505803
RN  - 0 (Calcium Phosphates)
RN  - 0 (Ccl2 protein, mouse)
RN  - 0 (Chemokine CCL2)
RN  - 0 (Interleukin-6)
RN  - 0 (Reactive Oxygen Species)
RN  - 0 (Transforming Growth Factor beta1)
RN  - 0 (interleukin-6, mouse)
RN  - 0LVT1QZ0BA (Homocysteine)
RN  - 97Z1WI3NDX (calcium phosphate)
RN  - EC 1.6.3.- (NADPH Oxidase 4)
RN  - EC 1.6.3.- (NADPH Oxidases)
RN  - EC 1.6.3.- (Nox4 protein, mouse)
RN  - EC 1.6.3.- (Nox4 protein, rat)
RN  - EC 3.4.19.12 (CYLD protein, mouse)
RN  - EC 3.4.19.12 (CYLD protein, rat)
RN  - EC 3.4.19.12 (Deubiquitinating Enzyme CYLD)
RN  - EC 3.4.19.12 (Ubiquitin Thiolesterase)
RN  - EC 3.4.22.- (Cysteine Endopeptidases)
SB  - IM
MH  - Adventitia/drug effects/*enzymology/pathology
MH  - Animals
MH  - Aortic Aneurysm, Abdominal/chemically induced/*enzymology/genetics/pathology
MH  - COS Cells
MH  - Calcium Phosphates
MH  - Cell Movement
MH  - *Cell Transdifferentiation/drug effects
MH  - Chemokine CCL2/metabolism
MH  - Chlorocebus aethiops
MH  - Cysteine Endopeptidases/deficiency/genetics/*metabolism
MH  - Deubiquitinating Enzyme CYLD
MH  - Disease Models, Animal
MH  - Dose-Response Relationship, Drug
MH  - Enzyme Stability
MH  - Extracellular Matrix/metabolism
MH  - Genotype
MH  - HEK293 Cells
MH  - Half-Life
MH  - Homocysteine/pharmacology
MH  - Humans
MH  - Hyperhomocysteinemia/complications/enzymology/genetics
MH  - Interleukin-6/metabolism
MH  - Male
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Myofibroblasts/drug effects/*enzymology/pathology
MH  - NADPH Oxidase 4
MH  - NADPH Oxidases/genetics/*metabolism
MH  - Phenotype
MH  - Proteolysis
MH  - RNA Interference
MH  - Rats, Sprague-Dawley
MH  - Reactive Oxygen Species/metabolism
MH  - Signal Transduction
MH  - Time Factors
MH  - Transfection
MH  - Transforming Growth Factor beta1/pharmacology
MH  - Ubiquitin Thiolesterase/genetics/*metabolism
MH  - Ubiquitination
MH  - *Vascular Remodeling/drug effects
OTO - NOTNLM
OT  - NADPH oxidase
OT  - adventitia
OT  - aneurysm
OT  - deubiquitinating enzymes
EDAT- 2017/07/29 06:00
MHDA- 2017/09/07 06:00
CRDT- 2017/07/29 06:00
PHST- 2016/08/26 00:00 [received]
PHST- 2017/07/13 00:00 [accepted]
PHST- 2017/07/29 06:00 [pubmed]
PHST- 2017/09/07 06:00 [medline]
PHST- 2017/07/29 06:00 [entrez]
AID - ATVBAHA.117.309859 [pii]
AID - 10.1161/ATVBAHA.117.309859 [doi]
PST - ppublish
SO  - Arterioscler Thromb Vasc Biol. 2017 Sep;37(9):1698-1709. doi: 
      10.1161/ATVBAHA.117.309859. Epub 2017 Jul 27.