Published Online
on November 24, 2003

A more recent version of this article appeared on December 2, 2003

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Submitted on March 24, 2003
Revised on June 24, 2003
Accepted on August 1, 2003

Activation of Apoptosis Signal-Regulating Kinase 1 in Injured Artery and Its Critical Role in Neointimal Hyperplasia

Yasukatsu Izumi MD, PhD, Shokei Kim MD, PhD^*, Minoru Yoshiyama MD, PhD, Yasuhiro Izumiya MD, Kaoru Yoshida MD, Atsushi Matsuzawa PhD, Hidenori Koyama MD, PhD, Yoshiki Nishizawa MD, PhD, Hidenori Ichijo PhD, Junichi Yoshikawa MD, PhD, and Hiroshi Iwao MD, PhD

From the Departments of Pharmacology (Y.I., S.K., Y.I., K.Y., H. Iwo), Cardiology and Internal Medicine (M.Y., J.Y.), and Metabolism, Endocrinology, and Molecular Medicine (H.K., Y.N.), Osaka City University Graduate School of Medicine, Osaka, and Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences (A.M., H. Ichijo), University of Tokyo, Japan.

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

Background--Apoptosis signal-regulating kinase 1 (ASK1), recently identified as one of the mitogen-activated protein kinase kinase kinases, is activated by various extracellular stimuli and involved in a variety of cellular function. Therefore, we first examined the role of ASK1 in vascular remodeling.

Methods and Results--We used rat balloon injury model and cultured vascular smooth muscle cells (VSMCs). Arterial ASK1 activity was rapidly and dramatically increased after balloon injury. To specifically inhibit endogenous ASK1 activation, dominant-negative mutant of ASK1 (DN-ASK1) was transfected into rat carotid artery before balloon injury. Gene transfer of DN-ASK1 significantly prevented neointimal formation at 14 days after injury. Bromodeoxyuridine labeling index at 7 days after injury showed that DN-ASK1 remarkably suppressed VSMC proliferation in both the intima and the media. We also examined the role of ASK1 in cultured rat VSMCs. Infection with DN-ASK1 significantly attenuated serum-induced VSMC proliferation and migration. We also compared neointimal formation after cuff placement around the femoral artery between mice deficient in ASK1 (ASK1^-/- mice) and wild-type (WT) mice. Neointimal formation at 28 days after cuff injury in ASK1^-/- mice was significantly attenuated compared with WT mice. Furthermore, we compared the proliferation and migration of VSMCs isolated from ASK1^-/- mice with WT mice. Both proliferation and migration of VSMCs from ASK1^-/- mice were significantly attenuated compared with VSMCs from WT mice.

Conclusions--ASK1 activation plays the key role in vascular intimal hyperplasia. ASK1 may provide the basis for the development of new therapeutic strategy for vascular diseases.

Key words: balloon • muscle, smooth • remodeling • signal transduction

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