Important role of apoptosis signal-regulating kinase 1 in ischemia-induced angiogenesis
Important role of apoptosis signal-regulating kinase 1 in ischemia-induced angiogenesis
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DOI：
10.1161/01.atv.0000174801.76234.bd
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发表时间：
2005-09-01
影响因子：
8.7
通讯作者：
Iwao, H
中科院分区：
文献类型：
--
作者：
Izumi, Y;Kim-Mitsuyama, S;Iwao, H
目的-我们首先研究了凋亡信号调节激酶1（ASK 1），有丝分裂原活化蛋白激酶之一，在缺血诱导的血管生成的作用。方法和结果-单侧后肢缺血手术诱导C57 BL/6 J野生型（WT）小鼠或小鼠缺乏ASK 1（ASK 1（-/-））。缺血后WT小鼠后肢的ASK 1活性显著增加。通过激光多普勒分析，观察到发育良好的侧支血管和血管生成在WT小鼠中对后肢缺血的反应，而这些反应在ASK 1（-/-）小鼠中减少。免疫组化结果显示，与WT小鼠相比，ASK 1（-/-）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，ASK 1（-/-）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，显性阴性ASK 1显著减弱过氧化氢诱导的VEGF和MCP-1的产生。此外，在体内阻断MCP-1的中和抗体抑制缺血后的血流和毛细血管形成的恢复。结论-ASK 1通路促进早期血管生成诱导炎性细胞浸润和VEGF和MCP-1的表达。ASK 1可能为开发新的血管生成治疗策略提供基础。
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.