Inhibition of protein tyrosine phosphatase improves angiogenesis via enhancing Ang-1/Tie-2 signaling in diabetes.

Experimental Diabetes Research Pub Date : 2012-01-01 Epub Date: 2012-02-12 DOI:10.1155/2012/836759
Jian-Xiong Chen, Qinhui Tuo, Duan-Fang Liao, Heng Zeng
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引用次数: 27

Abstract

Diabetes is associated with impairment of angiogenesis such as reduction of myocardial capillary formation. Our previous studies demonstrate that disruption of Angiopoietin-1 (Ang-1)/Tie-2 signaling pathway contributes to the diabetes-associated impairment of angiogenesis. Protein tyrosine phosphatase (PTP) has a critical role in the regulation of insulin signal by inhibition of tyrosine kinase phosphorylation. In present study, we examined the role of protein tyrosine phosphatase-1 (SHP-1) in diabetes-associated impairment of Ang-1/Tie-2 angiogenic signaling and angiogenesis. SHP-1 expression was significantly increased in diabetic db/db mouse hearts. Furthermore, SHP-1 bond to Tie-2 receptor and stimulation with Ang-1 led to SHP-1 dissociation from Tie-2 in mouse heart microvascular endothelial cell (MHMEC). Exposure of MHMEC to high glucose (HG, 30 mmol/L) increased SHP-1/Tie-2 association accompanied by a significant reduction of Tie-2 phosphorylation. Exposure of MHMEC to HG also blunted Ang-1-mediated SHP-1/Tie-2 dissociation. Knockdown of SHP-1 significantly attenuated HG-induced caspase-3 activation and apoptosis in MHMEC. Treatment with PTP inhibitors restored Ang-1-induced Akt/eNOS phosphorylation and angiogenesis. Our data implicate a critical role of SHP-1 in diabetes-associated vascular complications, and that upregulation of Ang-1/Tie-2 signaling by targeting SHP-1 should be considered as a new therapeutic strategy for the treatment of diabetes-associated impairment of angiogenesis.

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抑制蛋白酪氨酸磷酸酶通过增强糖尿病患者的Ang-1/Tie-2信号通路促进血管生成。
糖尿病与血管生成障碍有关,如心肌毛细血管形成减少。我们之前的研究表明,血管生成素-1 (ang1)/Tie-2信号通路的破坏有助于糖尿病相关的血管生成损伤。蛋白酪氨酸磷酸酶(Protein tyrosine phosphatase, PTP)通过抑制酪氨酸激酶磷酸化,在胰岛素信号调控中起关键作用。在本研究中,我们研究了蛋白酪氨酸磷酸酶-1 (SHP-1)在糖尿病相关的Ang-1/Tie-2血管生成信号和血管生成损伤中的作用。SHP-1在糖尿病小鼠心脏中表达显著升高。此外,SHP-1与Tie-2受体的结合和ang1的刺激导致SHP-1在小鼠心脏微血管内皮细胞(MHMEC)中与Tie-2分离。MHMEC暴露于高葡萄糖(HG, 30 mmol/L)会增加SHP-1/Tie-2的关联,同时Tie-2磷酸化显著降低。MHMEC暴露于HG也会减弱ang -1介导的SHP-1/Tie-2解离。敲低SHP-1可显著减弱hg诱导的MHMEC中caspase-3的激活和凋亡。PTP抑制剂可恢复ang -1诱导的Akt/eNOS磷酸化和血管生成。我们的数据暗示了SHP-1在糖尿病相关血管并发症中的关键作用,并且通过靶向SHP-1上调Ang-1/Tie-2信号传导应被视为治疗糖尿病相关血管生成损伤的新治疗策略。
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来源期刊
Experimental Diabetes Research
Experimental Diabetes Research 医学-内分泌学与代谢
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