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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:2184.)
© 2007 American Heart Association, Inc.

Vascular Biology

Ubiquitin Carboxyl-Terminal Hydrolase L1, a Novel Deubiquitinating Enzyme in the Vasculature, Attenuates NF-B Activation

Yoichi Takami; Hironori Nakagami; Ryuichi Morishita; Tomohiro Katsuya; Tai-Xing Cui; Tomonaga Ichikawa; Yukihiro Saito; Hiroki Hayashi; Yasushi Kikuchi; Tomoyuki Nishikawa; Yoshichika Baba; Osamu Yasuda; Hiromi Rakugi; Toshio Ogihara; Yasufumi Kaneda

From the Department of Geriatric Medicine (Y.T., T.K., Y.B., O.Y., H.R., T.O.), Osaka University Graduate School of Medicine, Japan; the Division of Gene Therapy Science (Y.T., H.N., Y.S., H.H., Y.K., T.N., Y.K.), Osaka University Graduate School of Medicine, Japan; the Division of Clinical Gene Therapy (R.M.), Osaka University Graduate School of Medicine, Japan; and Cardiovascular Medicine (T.-X.C., T.I.), University of Michigan Medical Center, Ann Arbor.

Correspondence to Hironori Nakagami, MD, PhD, Department of Gene Therapy Science, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita 565-0871, Japan. E-mail nakagami{at}gts.med.osaka-u.ac.jp

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-B (NF-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)-–induced NF-B activity in vascular cells and increased inhibitor of kappa B- (IB-), possibly through the attenuation of IB- ubiquitination, leading to decreased neointima in the balloon-injured artery. In contrast, knockdown of UCHL1 by small interfering RNA resulted in increased NF-B activity in VSMCs.

Conclusions— These data suggest that UCHL1 may partially attenuate vascular remodeling through inhibition of NF-B activity.

The ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) gene encodes for a deubiquitinating enzyme and is associated with Parkinson disease. UCHL1 gene expression was characterized in the neointima of the balloon-injured artery and in human atherosclerotic lesions. In vascular cells, UCHL1 attenuated TNF-–induced NF-B activity, possibly through the attenuation of IB- ubiquitination.

Key Words: UCHL1 • NF-B • deubiquitinating enzyme • atherosclerosis

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