Ubiquitin carboxyl-terminal hydrolase L1, a novel deubiquitinating enzyme in the vasculature, attenuates NF-κB activation
Ubiquitin carboxyl-terminal hydrolase L1, a novel deubiquitinating enzyme in the vasculature, attenuates NF-κB activation
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DOI：
10.1161/atvbaha.107.142505
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发表时间：
2007-10-01
影响因子：
8.7
通讯作者：
Kaneda, Yasufumi
中科院分区：
文献类型：
--
作者：
Takami, Yoichi;Nakagami, Hironori;Kaneda, Yasufumi
目的：通过对人内皮细胞（EC） cDNA文库的功能筛选，鉴定了一个编码去泛素化酶并在血管中表达的泛素羧基末端水解酶L1 （UCHL1）基因。UCHL1在神经元中表达，UCHL1的异常通过其对泛素-蛋白酶体系统的影响而导致遗传性帕金森病。因此，本研究的目的是通过评估核因子- κ B （nf - κ B）在内皮细胞和血管平滑肌细胞（VSMCs）中的失活来阐明UCHL1基因在血管重塑中的作用。方法和结果：通过Northern blot和免疫组化分析，UCHL1基因在血管内皮细胞、VSMCs和脑组织中内源性表达。UCHL1的表达在球囊损伤的颈动脉新生内膜中显著升高，也存在于人颈动脉粥样硬化病变中。UCHL1基因的过表达显著减弱肿瘤坏死因子(TNF)- α诱导的血管细胞NF-kappa B活性，增加kappa B- α抑制剂（I kappa B- α），可能是通过I kappa B- α泛素化的衰减，导致球囊损伤动脉内新内膜减少。相比之下，通过小干扰RNA敲低UCHL1导致VSMCs中nf - κ B活性增加。结论：这些数据表明，UCHL1可能通过抑制nf - κ B活性部分减弱血管重构。
Objective-We identified a ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) gene, which encodes a deubiquitinating enzyme and is expressed in the vasculature, by functional screening of a human endothelial cell (EC) cDNA library. UCHL1 is expressed in neurons, and abnormalities in UCHL1 are responsible for inherited Parkinson's disease via its effects on the ubiquitin-proteasome system. Therefore, the goal of present study was to clarify the role of the UCHL1 gene in vascular remodeling by evaluating nuclear factor-kappa B (NF-kappa B) inactivation in ECs and vascular smooth muscle cells (VSMCs).Methods and Results-From Northern blot and immunohistochemical analysis, the UCHL1 gene was endogenously expressed in vascular ECs, VSMCs, and brain tissue. Expression of UCHL1 was markedly increased in the neointima of the balloon-injured carotid artery and was also present in atherosclerotic lesions from human carotid arteries. Overexpression of the UCHL1 gene significantly attenuated tumor necrosis factor (TNF)-alpha- induced NF-kappa B activity in vascular cells and increased inhibitor of kappa B-alpha (I kappa B-alpha), possibly through the attenuation of I kappa B-alpha ubiquitination, leading to decreased neointima in the balloon-injured artery. In contrast, knockdown of UCHL1 by small interfering RNA resulted in increased NF-kappa B activity in VSMCs.Conclusions-These data suggest that UCHL1 may partially attenuate vascular remodeling through inhibition of NF-kappa B activity.