| First Author | Yu B | Year | 2017 |
| Journal | Arterioscler Thromb Vasc Biol | Volume | 37 |
| Issue | 9 | Pages | 1698-1709 |
| PubMed ID | 28751569 | Mgi Jnum | J:269258 |
| Mgi Id | MGI:6272180 | Doi | 10.1161/ATVBAHA.117.309859 |
| Citation | Yu B, et al. (2017) CYLD Deubiquitinates Nicotinamide Adenine Dinucleotide Phosphate Oxidase 4 Contributing to Adventitial Remodeling. Arterioscler Thromb Vasc Biol 37(9):1698-1709 |
| abstractText | 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 CaPO4-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. |
