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

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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.

Original languageEnglish
Pages (from-to)1877-1883
Number of pages7
JournalArteriosclerosis, thrombosis, and vascular biology
Issue number9
Publication statusPublished - 2005 Sep


  • Angiogenesis
  • Cytokines
  • Inflammation
  • Ischemia
  • Signal transduction

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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    Izumi, Y., Kim-Mitsuyama, S., Yoshiyama, M., Omura, T., Shiota, M., Matsuzawa, A., Yukimura, T., Murohara, T., Takeya, M., Ichijo, H., Yoshikawa, J., & Iwao, H. (2005). Important role of apoptosis signal-regulating kinase 1 in ischemia-induced angiogenesis. Arteriosclerosis, thrombosis, and vascular biology, 25(9), 1877-1883.