on June 23, 2005
Published online before print June 23, 2005, doi: 10.1161/01.ATV.0000174801.76234.bd
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Submitted on December 27, 2004
Accepted on June 1, 2005
Important Role of Apoptosis Signal-Regulating Kinase 1 in Ischemia-Induced Angiogenesis
Yasukatsu Izumi ;
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.
* To whom correspondence should be addressed. 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.
Key words: angiogenesis • ischemia • inflammation • signal transduction • cytokines
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