Izumi Yasukatsu, Kim-Mitsuyama Shokei, Yoshiyama Minoru, Omura Takashi, Shiota Masayuki, Matsuzawa Atsushi, Yukimura Tokihito, Murohara Toyoaki, Takeya Motohiro, Ichijo Hidenori, Yoshikawa Junichi, Iwao Hiroshi
Department of Pharmacology, Osaka City University Medical School, Japan.
Arterioscler Thromb Vasc Biol. 2005 Sep;25(9):1877-83. doi: 10.1161/01.ATV.0000174801.76234.bd. Epub 2005 Jun 23.
We first examined the role of apoptosis signal-regulating kinase 1 (ASK1), one of mitogen-activated protein kinase kinase kinases, in ischemia-induced angiogenesis.
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.
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.
我们首先研究了有丝分裂原活化蛋白激酶激酶激酶之一的凋亡信号调节激酶1（ASK1）在缺血诱导的血管生成中的作用。
通过手术诱导C57BL/6J野生型（WT）小鼠或ASK1基因缺陷小鼠（ASK1(-/-)）单侧后肢缺血。缺血后WT小鼠后肢的ASK1活性显著增加。通过激光多普勒分析，WT小鼠对后肢缺血有反应，出现了发育良好的侧支血管和血管生成，而ASK1(-/-)小鼠的这些反应减弱。免疫染色显示，与WT小鼠相比，ASK1(-/-)小鼠缺血组织中巨噬细胞和T淋巴细胞的浸润受到抑制。与WT小鼠相比，ASK1(-/-)小鼠缺血组织中血管内皮生长因子（VEGF）和单核细胞趋化蛋白-1（MCP-1）蛋白的表达较弱。对内皮细胞的体外研究表明，显性负性ASK1显著减弱了过氧化氢诱导的VEGF和MCP-1的产生。此外，用其中和抗体在体内阻断MCP-1可抑制缺血后血流恢复和毛细血管形成。
ASK1通路通过诱导炎症细胞浸润以及VEGF和MCP-1表达促进早期血管生成。ASK1可能为开发新的血管生成治疗策略提供依据。
