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(Circulation. 2005;111:1672-1678.)
© 2005 American Heart Association, Inc.

Vascular Medicine

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; 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.

Correspondence to Tetsuo Minamino, MD, PhD, Division of Cardiology, Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan. E-mail minamino{at}medone.med.osaka-u.ac.jp

Received August 26, 2004; revision received November 16, 2004; accepted November 18, 2004.

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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