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. 2003 Dec 2;108(22):2812-8.
doi: 10.1161/01.CIR.0000096486.01652.FC. Epub 2003 Nov 24.

Activation of apoptosis signal-regulating kinase 1 in injured artery and its critical role in neointimal hyperplasia

Yasukatsu Izumi  1 , Shokei Kim, Minoru Yoshiyama, Yasuhiro Izumiya, Kaoru Yoshida, Atsushi Matsuzawa, Hidenori Koyama, Yoshiki Nishizawa, Hidenori Ichijo, Junichi Yoshikawa, Hiroshi Iwao
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Activation of apoptosis signal-regulating kinase 1 in injured artery and its critical role in neointimal hyperplasia

Yasukatsu Izumi et al. Circulation. .

Abstract

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.

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