Specific inhibition of plasminogen activator inhibitor 1 reduces blood glucose level by lowering TNF-a
Specific inhibition of plasminogen activator inhibitor 1 reduces blood glucose level by lowering TNF-a
复制标题
纤溶酶原激活剂抑制剂 1 的特异性抑制可通过降低 TNF-a 来降低血糖水平
DOI：
10.1016/j.lfs.2020.117404
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发表时间：
2020
期刊：
影响因子：
6.1
通讯作者：
Chen Zhuo
中科院分区：
文献类型：
--
作者：
Tang Shuzhi;Liu Wenzhen;Pan Xiaohong;Liu Libin;Yang Yongshuai;Wang Dong;Xu Peng;Huang Mingdong;Chen Zhuo
目的探讨纤溶酶原激活物抑制剂1 （PAI-1）对2型糖尿病（T2DM）血糖的影响及其机制。材料与方法我们以失活的尿激酶为基础，开发了一种高效、高特异性的PAI-1抑制剂，命名为PAItrap3。同时，平行制备PAItrap3单点突变（即PAItrapNC）作为阴性对照。将PAItrap3静脉注射到2型糖尿病（T2D）小鼠体内，通过测量T2D小鼠的血糖、PAI-1和肿瘤坏死因子α (TNF-α)水平来评估其对代谢系统的影响。关键发现spaitrap3显著降低链脲佐菌素诱导的t2dm小鼠的高血糖水平和PAI-1水平。PAItrapNC对t2dm小鼠无降糖作用。机制上，PAItrap3可降低PAI-1和TNF-α水平。此外，我们观察到PAItrap3减少了脂肪细胞中脂肪滴的数量。意义这些发现为PAI-1参与炎症和肥胖介导的高血糖提供了明确的证据，为抑制PAI-1治疗T2DM开辟了新的前景。
AimsThe study aims to investigate the effect of plasminogen activator inhibitor 1 (PAI-1), a primary inhibitor of fibrinolytic process, on blood glucose in type 2 diabetes mellitus (T2DM) and its mechanism.Materials and methodsWe developed a highly potent and highly specific PAI-1 inhibitor, named PAItrap3, based on the inactivated urokinase. Meanwhile, a single point mutation of PAItrap3 (i.e., PAItrapNC) was parallelly prepared as negative control. PAItrap3 was intravenously injected into type 2 diabetic (T2D) mice and its effect on metabolic system was evaluated by measuring the levels of blood glucose, PAI-1, and tumor necrosis factor alpha (TNF-α) in T2D mice.Key findingsPAItrap3 significantly reduced the high blood glucose level and PAI-1 level in streptozotocin-induced T2D mice. PAItrapNC did not have any hypoglycemic effect at all on T2D mice. Mechanistically, both PAI-1 and TNF-α levels were attenuated by the administration of PAItrap3. In addition, we observed that PAItrap3 reduced the amount of fat droplets in adipocytes.SignificanceThese findings provide clear evidence for PAI-1 to participate in inflammation and obesity mediated hyperglycemia, and open up a new prospect for the treatment of T2DM by PAI-1 inhibition.