SiRNA targeting SHP-1 accelerates angiogenesis in a rat model of hindlimb ischemia
SiRNA targeting SHP-1 accelerates angiogenesis in a rat model of hindlimb ischemia
复制标题
DOI：
10.1016/j.atherosclerosis.2006.04.021
复制
发表时间：
2007-03-01
期刊：
影响因子：
5.3
通讯作者：
Makino, Naoki
中科院分区：
文献类型：
--
作者：
Sugano, Masahiro;Tsuchida, Keiko;Makino, Naoki
血管内皮生长因子（VEGF）受体-2（KDR/flk-1）具有酪氨酸激酶结构域，一旦被激活，其诱导酪氨酸残基的自磷酸化，这是血管生成所必需的。SHP-1是一种胞质蛋白酪氨酸磷酸酶，通过其结合的受体的去磷酸化在信号转导途径中起负调节作用。因此，设计用于抑制SHP-1表达的治疗性血管生成在后肢缺血中将是有益的。在体外，SHP-1 siRNA抑制SHP-1削弱了TNF阻断VEGF诱导的KDR/flk-1酪氨酸磷酸化的能力，并显示出内皮细胞生长的增加。在体内，在大鼠后肢缺血模型中，SHP-1 mRNA、SHP-1蛋白水平和VEGF增加。注射到缺血性闭肌后，基于载体的siRNA减少了SHP-1，增加了KDR/flk-1的磷酸化，并显著增加了毛细血管密度。我们的数据表明，在体内的潜在用途的siRNA靶向SHP-1作为外周缺血性疾病的治疗。(c)2006爱思唯尔爱尔兰有限公司保留所有权利。
Vascular endothelial growth factor (VEGF) receptor-2 (KDR/flk-1) has a tyrosine kinase domain, and once activated, induces the autophosphorylation of the tyrosine residues, which is essential for angiogenesis. SHP-1, a cytoplasmic protein tyrosine phosphatase, plays a negative regulatory role in signal transduction pathways by dephosphorylation of the receptors to which it binds. Thus, therapeutic angiogenesis designed to inhibit expression of SHP-1 would be beneficial in hindlimb ischemia. In in vitro, the inhibition of SHP-1 by SHP-1 siRNA impaired the ability of TNF to block the tyrosine phosphorylation of KDR/flk-1 induced by VEGF and showed an increase in endothelial cell growth. In in vivo, SHP-1 mRNA, SHP-1 protein levels and VEGF were increased in a rat model of hindlimb ischemia. Upon injection to the ischemic adductor muscle, vector-based siRNA reduced SHP-1, increased phosphorylation of KDR/flk-1, and markedly increased capillary density. Our data demonstrated in vivo the potential use of siRNA targeting SHP-1 as therapy for peripheral ischemic diseases. (c) 2006 Elsevier Ireland Ltd. All rights reserved.