CYLD Deubiquitinates Nicotinamide Adenine Dinucleotide Phosphate Oxidase 4 Contributing to Adventitial Remodeling.
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.Transforming growth factor-β1 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-β1-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-β1 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 CaPO4-induced abdominal aortic aneurysm in mice. These effects were abolished in CYLD-/- mice.CYLD contributes to the transdifferentiation of AFs via deubiquitinating Nox4 and may play a role in vascular remodeling.
Mesh Terms:
Adventitia, Animals, Aortic Aneurysm, Abdominal, COS Cells, Calcium Phosphates, Cell Movement, Cell Transdifferentiation, Cercopithecus aethiops, Chemokine CCL2, Cysteine Endopeptidases, Disease Models, Animal, Dose-Response Relationship, Drug, Enzyme Stability, Extracellular Matrix, Genotype, HEK293 Cells, Half-Life, Homocysteine, Humans, Hyperhomocysteinemia, Interleukin-6, Male, Mice, Inbred C57BL, Mice, Knockout, Myofibroblasts, NADPH Oxidase 4, NADPH Oxidases, Phenotype, Proteolysis, RNA Interference, Rats, Sprague-Dawley, Reactive Oxygen Species, Signal Transduction, Time Factors, Transfection, Transforming Growth Factor beta1, Ubiquitin Thiolesterase, Ubiquitination, Vascular Remodeling
Adventitia, Animals, Aortic Aneurysm, Abdominal, COS Cells, Calcium Phosphates, Cell Movement, Cell Transdifferentiation, Cercopithecus aethiops, Chemokine CCL2, Cysteine Endopeptidases, Disease Models, Animal, Dose-Response Relationship, Drug, Enzyme Stability, Extracellular Matrix, Genotype, HEK293 Cells, Half-Life, Homocysteine, Humans, Hyperhomocysteinemia, Interleukin-6, Male, Mice, Inbred C57BL, Mice, Knockout, Myofibroblasts, NADPH Oxidase 4, NADPH Oxidases, Phenotype, Proteolysis, RNA Interference, Rats, Sprague-Dawley, Reactive Oxygen Species, Signal Transduction, Time Factors, Transfection, Transforming Growth Factor beta1, Ubiquitin Thiolesterase, Ubiquitination, Vascular Remodeling
Arterioscler. Thromb. Vasc. Biol.
Date: Dec. 01, 2016
PubMed ID: 28751569
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