Plasminogen Activator Inhibitor-1 Protects Mice Against Cardiac Fibrosis by Inhibiting Urokinase-type Plasminogen Activator-mediated Plasminogen Activation.
Plasminogen Activator Inhibitor-1 Protects Mice Against Cardiac Fibrosis by Inhibiting Urokinase-type Plasminogen Activator-mediated Plasminogen Activation.
复制标题
DOI：
10.1038/s41598-017-00418-y
复制
发表时间：
2017-03-23
影响因子：
4.6
通讯作者：
Ploplis VA
中科院分区：
文献类型：
--
作者：
Gupta KK;Donahue DL;Sandoval-Cooper MJ;Castellino FJ;Ploplis VA
已知纤溶酶原激活剂抑制剂-1 (PAI-1) 可以保护小鼠免受心脏纤维化。据推测，PAI-1 可能通过灭活尿激酶型纤溶酶原激活剂 (uPA) 并最终抑制纤溶酶 (Pm) 的产生来调节心脏纤维化。然而，PAI-1 在心脏纤维化过程中使 uPA 失活并限制 Pm 产生的体内作用仍有待确定。本研究的目的是确定 PAI-1 的心脏保护作用是否是通过其直接调节尿激酶介导的纤溶酶原 (Pg) 激活的能力来介导的。本研究采用血管紧张素 II (AngII)-醛固酮 (Ald) 输注小鼠高血压模型。 AngII-Ald 输注 4 周后，PAI-1 缺陷 (PAI-1−/−) 小鼠出现严重的心脏纤维化。然而，在 PAI-1−/−/uPA−/− 双敲除小鼠中观察到心脏纤维化显着减少，这与炎症减少、与组织重塑相关的 TGF-β 和蛋白酶表达水平降低以及 Smad2 信号传导减弱有关。此外，在表达无活性纤溶酶（Pm）但酶原 Pg 水平正常（PAI-1−/−/PgS743A/S743A）的 PAI-1−/− 小鼠中观察到心脏纤维化的完全消融。我们的研究结果表明，PAI-1 通过抑制活性 Pm 的产生来保护小鼠免受高血压诱导的心脏纤维化。
Plasminogen activator inhibitor-1 (PAI-1) is known to protect mice against cardiac fibrosis. It has been speculated that PAI-1 may regulate cardiac fibrosis by inactivating urokinase-type plasminogen activator (uPA) and ultimately plasmin (Pm) generation. However, the in vivo role of PAI-1 in inactivating uPA and limiting the generation of Pm during cardiac fibrosis remains to be established. The objective of this study was to determine if the cardioprotective effect of PAI-1 is mediated through its ability to directly regulate urokinase -mediated activation of plasminogen (Pg). An Angiotensin II (AngII)-aldosterone (Ald) infusion mouse model of hypertension was utilised in this study. Four weeks after AngII-Ald infusion, PAI-1-deficient (PAI-1−/−) mice developed severe cardiac fibrosis. However, a marked reduction in cardiac fibrosis was observed in PAI-1−/−/uPA−/− double knockout mice that was associated with reduced inflammation, lower expression levels of TGF-β and proteases associated with tissue remodeling, and diminished Smad2 signaling. Moreover, total ablation of cardiac fibrosis was observed in PAI-1−/− mice that express inactive plasmin (Pm) but normal levels of zymogen Pg (PAI-1−/−/PgS743A/S743A). Our findings indicate that PAI-1 protects mice from hypertension-induced cardiac fibrosis by inhibiting the generation of active Pm.