Urokinase plasminogen activator independent early experimental thrombus resolution: MMP2 as an alternative mechanism.
Urokinase plasminogen activator independent early experimental thrombus resolution: MMP2 as an alternative mechanism.
复制标题
尿激酶纤溶酶原激活剂独立的早期实验性血栓溶解：MMP2 作为替代机制。
DOI：
10.1160/th10-03-0184
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发表时间：
2010
影响因子：
6.7
通讯作者：
Henke,PeterK
中科院分区：
文献类型：
--
作者：
Sood,Vikram;Luke,CatherineE;Deatrick,KBarry;Baldwin,Joseph;Miller,ErinM;Elfline,Megan;UpchurchJr,GilbertR;Wakefield,ThomasW;Henke,PeterK
深静脉血栓（DVT）的消退被认为主要是尿激酶纤溶酶原激活剂（uPA）依赖性机制，尽管观察表明可能存在其他非纤溶机制。我们探讨了基质金属蛋白酶 (MMP) -2 和 –9 在 uPA 缺陷小鼠早期 DVT 缓解中的作用。雄性 B6/SVEV (WT) 和基因匹配的 uPA -/- 小鼠接受下腔静脉 (IVC) 结扎以产生瘀滞静脉血栓，并采集 IVC 和血栓。第 4 天时，WT 小鼠和 uPA -/- 小鼠的血栓大小相似，表明早期非 uPA 依赖性消退。与 WT 相比，uPA -/- 小鼠中血栓内中性粒细胞和单核细胞减少了 3 倍和 3.5 倍。通过 ELISA，uPA -/- 小鼠的肿瘤坏死因子 α 和白细胞介素 1β 没有改变，而干扰素 (IFN) γ 显着升高。 uPA -/- 小鼠中未观察到血栓 tPA 代偿性增加，纤溶酶活性降低且 PAI-1 升高 2.5 倍。与 WT 以及 MMP-14（一种 MMP2 激活剂）相比，uPA-/- 小鼠中的活性 MMP2（而非 MMP9）升高了 3 倍。与WT相比，uPA -/- 小鼠血栓中IV型胶原蛋白和纤维蛋白原减少。 IFNγ诱导MMP2，与WT相比，IFNγ的阻断与更大的静脉血栓和活性MMP2减少相关。一致的是，尽管血栓纤溶酶水平正常，但与 WT 对照相比，MMP2 -/- 小鼠的 VT 更大。总而言之，早期实验性静脉血栓消退与 uPA 无关，部分与炎症细胞流入无关。 MMP2 依赖性溶栓是静脉血栓消退的重要代偿机制，可能通过 IV 型胶原代谢实现，并且可能代表一种可开发的治疗途径。
Deep-vein thrombosis (DVT) resolution is thought to be primarily a urokinase plasminogen activator (uPA) -dependent mechanism, although observations suggest other non-fibrinolytic mechanisms may exist. We explored the role of matrix metalloproteinase (MMP) -2 and –9 in early DVT resolution in uPA-deficient mice. Male B6/SVEV (WT) and genetically matched uPA -/- mice underwent inferior vena cava (IVC) ligation to create stasis venous thrombi, with IVC and thrombus harvest. Thrombus size was similar between WT and uPA -/- mice at day 4, suggesting early non uPA-dependent resolution. Intrathrombus neutrophils and monocytes were reduced 3- and 3.5-fold in uPA -/- mice as compared with WT. By ELISA, tumour necrosis factor α and interleukin 1β were not altered, while interferon (IFN)γ was significantly elevated in uPA -/- mice. A compensatory increase in thrombus tPA was not observed, plasmin activity was reduced and PAI-1 was elevated 2.5-fold in uPA -/- mice. Active MMP2, but not MMP9, was elevated 3-fold in uPA-/- mice as compared with WT as well as MMP-14, an MMP2 activator. Collagen type IV and fibrinogen were reduced in uPA -/- mice thrombi as compared with WT. IFNγ induces MMP2, and blockade of IFNγ was associated with larger venous thrombi and reduced active MMP2, as compared with WT. Consistently, MMP2 -/- mice had larger VT as compared with WT controls, despite normal thrombus plasmin levels. Taken together, early experimental venous thrombus resolution is independent of uPA, and, in part, inflammatory cell influx. MMP2-dependent thrombolysis is an important compensatory mechanism of venous thrombus resolution, possibly by collagen type IV metabolism, and may represent an exploitable therapeutic avenue.