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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:1877.)
© 2005 American Heart Association, Inc.

Vascular Biology

Important Role of Apoptosis Signal-Regulating Kinase 1 in Ischemia-Induced Angiogenesis

Yasukatsu Izumi; Shokei Kim-Mitsuyama; Minoru Yoshiyama; Takashi Omura; Masayuki Shiota; Atsushi Matsuzawa; Tokihito Yukimura; Toyoaki Murohara; Motohiro Takeya; Hidenori Ichijo; Junichi Yoshikawa; Hiroshi Iwao

From the Departments of Pharmacology (Y.I., M.S., H. Iwao) and Cardiology and Internal Medicine (M.Y., T.O., J.Y.), Osaka City University Medical School, Japan; the Departments of Pharmacology and Molecular Therapeutics (S.K.-M.) and Cell Pathology (M.T.), Kumamoto University Graduate School of Medical Sciences, Japan; Faculty of Education and Social Welfare (T.Y.), Ohtani Women’s University, Tondabayashi, Japan; the Department of Cardiology (T.M.), Nagoya University Graduate School of Medicine, Japan; and the Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences (A.M., H. Ichijo), University of Tokyo, Japan.

Correspondence to Shokei Kim-Mitsuyama, MD, Department of Pharmacology and Molecular Therapeutics, Kumamoto University Graduate School of Medical Sciences, 1-1-1 Honjo, Kumamoto 860-8556, Japan. E-mail kimmitsu{at}gpo.kumamoto-u.ac.jp

Objective— We first examined the role of apoptosis signal-regulating kinase 1 (ASK1), one of mitogen-activated protein kinase kinase kinases, in ischemia-induced angiogenesis.

Methods and Results— Unilateral hindlimb ischemia was induced surgically in C57BL/6J wild-type (WT) mice or mice deficient in ASK1 (ASK1^–/–). ASK1 activity in WT mouse hindlimb was increased dramatically after ischemia. By laser Doppler analysis, well-developed collateral vessels and angiogenesis were observed in WT mice in response to hindlimb ischemia, whereas these responses were reduced in ASK1^–/– mice. Immunostaining revealed that infiltration of macrophages and T lymphocytes was suppressed in the ischemic tissues of ASK1^–/– mice compared with WT mice. The expression of vascular endothelial growth factor (VEGF) and monocyte chemoattractant protein-1 (MCP-1) proteins in ischemic tissues was weaker in ASK1^–/– mice compared with WT mice. In vitro study on endothelial cells indicated that dominant-negative ASK1 significantly attenuated hydrogen peroxide–induced VEGF and MCP-1 production. Furthermore, in vivo blockade of MCP-1 by its neutralizing antibody suppressed the recovery of the blood flow and capillary formation after ischemia.

Conclusions— ASK1 pathway promotes early angiogenesis by inducing inflammatory cell infiltration and VEGF and MCP-1 expression. ASK1 may provide the basis for the development of new therapeutic strategy for angiogenesis.

We examined the significance of apoptosis signal-regulating kinase 1 (ASK1) in ischemia-induced angiogenesis in vivo. Well-developed collateral vessels and angiogenesis were observed in wild-type mice in response to hindlimb ischemia, whereas these responses were reduced in mice deficient in ASK1. Thus, the activation of ASK1 leads to angiogenesis.

Key Words: angiogenesis • ischemia • inflammation • signal transduction • cytokines

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