The effect of matrix metalloproteinase 2 and matrix metalloproteinase 2/9 deletion in experimental post-thrombotic vein wall remodeling.
The effect of matrix metalloproteinase 2 and matrix metalloproteinase 2/9 deletion in experimental post-thrombotic vein wall remodeling.
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DOI：
10.1016/j.jvs.2012.11.088
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发表时间：
2013-11
影响因子：
4.3
通讯作者：
Henke PK
中科院分区：
文献类型：
--
作者：
Deatrick KB;Luke CE;Elfline MA;Sood V;Baldwin J;Upchurch GR Jr;Jaffer FA;Wakefield TW;Henke PK
深静脉血栓形成（VT）后静脉壁纤维化损伤与基质金属蛋白酶（MMPs）升高相关。MMP 2是否以及通过何种机制参与VT后静脉壁重塑尚不清楚。通过结扎下腔静脉（IVC）产生淤滞性VT，并在MMP 2 −/−和遗传野生型（WT）小鼠的第2、8和21天收获组织。通过免疫组织化学、ELISA、真实的时间PCR和酶谱法进行组织分析。与WT相比，MMP 2-/-组在8天时血栓消退受损，VT大小增加51%（p < .01），vWF阳性通道减少3倍（p<.05）。在MMP 2 −/−小鼠中，主要的表型纤维化差异发生在VT后8天，与WT相比，静脉壁胶原蛋白含量显著降低（p= 0.013），III型前胶原基因表达降低4倍（p <0.01），但I型前胶原没有差异。VT后第2天和第8天，TNFα和IL 1 β降低约3倍，提示MMP 2 −/−静脉壁炎症减轻（p < .05）。与WT相比，MMP 2 −/−组静脉壁单核细胞增加4倍（p = 0.03），凋亡减少3倍（p <0.05），但在8天时细胞增殖无差异。由于在MMP 2 −/−小鼠中观察到MMP 9代偿性活性增加，MMP 2/9双无效小鼠在第8天用VT收获物诱导血栓。一致地，发现VT增大2倍，静脉壁胶原减少3倍，单核细胞增加3倍（均p <0.05）。在给予外源性MMP 2抑制剂的MMP 9 −/−小鼠中观察到类似的发现。在静止性室性心动过速中，尽管单核细胞增加，但MMP 2的缺失与较少的中期静脉壁纤维化和炎症相关。考虑到MMP 2（和MMP 2/9）缺失会损害VT消退，表明直接抑制可能也需要抗凝治疗。
Vein wall fibrotic injury following deep venous thrombosis (VT) is associated with elevated matrix metalloproteinases (MMPs). Whether and by what mechanism MMP2 contributes to vein wall remodeling after VT is unknown. Stasis VT was produced by ligation of the inferior vena cava (IVC) and tissue was harvested at 2, 8, and 21 days in MMP2 −/− and genetic wild type (WT) mice. Tissue analysis by immunohistochemistry, ELISA, real time PCR, and zymography was performed. Thrombus resolution was impaired at 8d in MMP2 −/− as compared with WT, evidenced by a 51% increase in VT size (p < .01), and 3 fold fewer vWF positive channels (p<.05). In MMP2 −/− mice, the main phenotypic fibrotic differences occurred at 8d post VT, with significantly less vein wall collagen content (p=.013), 4 fold lower procollagen III gene expression (p < .01) but no difference in procollagen I as compared to WT. Decreased inflammation in MMP2−/− vein walls was suggested by ~ 3 fold reduced TNFα and IL1β at 2d and 8d post VT (p < .05). A 4 fold increase in vein wall monocytes (p = .03) with 3 fold decreased apoptosis (p < .05), but no difference in cellular proliferation at 8d was found in MMP2−/− as compared with WT. As increased compensatory MMP9 activity was observed in the MMP2 −/− mice, MMP2/9 double null mice had thrombus induced with VT harvest at 8d. Consistently, 2 fold larger VT, a 3 fold decrease in vein wall collagen, and a 3 fold increase in monocytes was found (all p < .05). Similar findings were observed in MMP9 −/− mice administered an exogenous MMP2 inhibitor. In stasis VT, deletion of MMP2 was associated with less midterm vein wall fibrosis and inflammation, despite an increase in monocytes. Consideration that VT resolution was impaired with MMP2 (and MMP2/9) deletion suggests direct inhibition will likely also require anticoagulant therapy.
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影响因子：
20.1
作者：
Cho, A;Reidy, MA
通讯作者：
Reidy, MA
影响因子：
2.9
作者：
Cuttle, L;Nataatmadja, M;Hayes, MT
通讯作者：
Hayes, MT
影响因子：
2.2
作者：
Dewyer, Nicholas A.;Sood, Vikram;Henke, Peter K.
通讯作者：
Henke, Peter K.
影响因子：
4.3
作者：
Myers, Daniel D., Jr.;Henke, Peter K.;Wakefield, Thomas W.
通讯作者：
Wakefield, Thomas W.
影响因子：
4.3
作者：
CASTAGNOLI, C;STELLA, M;RICHIARDI, PM
通讯作者：
RICHIARDI, PM