Published Online
on March 28, 2005

A more recent version of this article appeared on April 5, 2005

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Submitted on August 26, 2004
Revised on November 16, 2004
Accepted on November 18, 2004

Ablation of MEK Kinase 1 Suppresses Intimal Hyperplasia by Impairing Smooth Muscle Cell Migration and Urokinase Plasminogen Activator Expression in a Mouse Blood-Flow Cessation Model

Yan Li MD, PhD, Tetsuo Minamino MD, PhD^*, Osamu Tsukamoto MD, Toshiaki Yujiri MD, PhD, Yasunori Shintani MD, Ken-ichiro Okada MD, Yoko Nagamachi BS, Masashi Fujita MD, Akio Hirata MD, Shoji Sanada MD, PhD, Hiroshi Asanuma MD, PhD, Seiji Takashima MD, PhD, Masatsugu Hori MD, PhD, Gary L. Johnson PhD, and Masafumi Kitakaze MD, PhD

From the Department of Internal Medicine and Therapeutics (Y.L., T.M., O.T., Y.S., K.-i.O., Y.N., M.F., A.H., S.S., H.A., S.T., M.H.), Osaka University Graduate School of Medicine, Suita, Osaka, Japan; the Department of Cardiovascular Medicine (M.K.), National Cardiovascular Center, Suita, Osaka, Japan; the Department of Cardiology (Y.L.), Xijing Hospital, Forth Military Medical University, Xi’an, People’s Republic of China; the Department of Bio-Signal Analysis (T.Y.), Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan; and the Department of Pharmacology (G.L.J.), University of North Carolina School of Medicine, Chapel Hill, NC.

^* To whom correspondence should be addressed. E-mail: minamino{at}medone.med.osaka-u.ac.jp.

Background--Migration, proliferation, and matrix-degrading protease expression of smooth muscle cells (SMCs) are major features of intimal hyperplasia after vascular injury. Although MEK kinase 1 (MEKK1) has been shown to regulate cell migration and urokinase plasminogen activator (uPA) expression, the precise role of MEKK1 in this process remains unknown.

Methods and Results--We triggered a vascular remodeling model by complete ligation of the right common carotid artery in wild-type (WT) and MEKK1-null (MEKK1^-/-) mice. The intimal areas 28 days after ligation were significantly decreased in the ligated MEKK1^-/- arteries compared with WT arteries (28±8 versus 65±17 µm², P<0.05). There were no differences in the ratios of proliferating cell nuclear antigen (PCNA)-positive cells to total cells within the arterial wall between WT and MEKK1^-/- arteries. Proliferation capacity also did not differ between WT and MEKK1^-/- cultured aortic smooth muscle cells (AoSMCs). In contrast, the number of intimal PCNA-positive cells 7 days after ligation was significantly smaller in MEKK1^-/- arteries. Three different migration assays revealed that migration and invasion of MEKK1^-/- AoSMCs were markedly impaired. Addition of full-length MEKK1 restored the migration capacity of MEKK1^-/- AoSMCs. The number of MEKK1^-/- AoSMCs showing lamellipodia formation by epithelial growth factor was significantly smaller compared with those of WT SMCs. Furthermore, uPA expression after ligation was markedly decreased in MEKK1^-/- arteries.

Conclusions--MEKK1 is implicated in vascular remodeling after blood-flow cessation by regulating the migration and uPA expression of SMCs. MEKK1 is a potential target for drug development to prevent vascular remodeling.

Key words: remodeling • muscle, smooth • vasculature • restenosis

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