抗阻运动下调miR-92a-3p介导内皮细胞HMOX1/MAPKs/NF-κB预防导管相关性血栓形成的机制研究

Catheter-related thrombosis(CRT) is the most severe complication of central venous access devices. Insertion of intravascular catheter can cause hemodynamic changes and contribute to venous thrombosis. Many studies have shown that exercise can prevent CRT, but the molecular mechanism remains unclear. MiR-92a-3p was upregulated in vein thrombosis tissues. And shear stress could be down-regulate miR-92a-3p in endothelial cells. Based on our previous studies, we found resistance exercise could change shear stress, down-regulate miR-92a-3p, and prevent CRT. Using bioinformatics algorithms, we found HMOX1 was predicted as a putative target of miR-92a-3p. Studies show HMOX1 can inhibit venous thrombosis. Accordingly, we hypothesize that resistance exercise prevents the development of CRT through down-regulation of miR-92a-3p in endothelial cells targeting HMOX1 and regulating downstream molecular induced by shear stress. We plan to explore the mechanism of resistance exercise preventing CRT through experimental techniques, including introduction and interference of gene as well ae exercise intervention of animal model etc, in molecule, cell and animal level as to elucidate the biological function of shear stress, miR-92a-3p-HMOX1 cascade in CRT formation and provide a theoretical basis for CRT prevention.

导管相关性血栓（CRT）是中心静脉导管最严重的并发症。血管内导管置入可引起血流动力学变化，促使CRT形成。研究表明，运动能预防CRT，但其分子机制尚未明确。miR-92a-3p在血栓组织中表达升高，而增加血流切应力能下调miR-92a-3p的表达。我们前期研究发现，抗阻运动能改变血流切应力，降低内皮细胞miR-92a-3p表达，预防CRT；经生物信息学预测，发现血红素加氧酶（HMOX1）是miR-92a-3p可能的靶基因，且有研究表明HMOX1可以抑制静脉血栓形成。据此，我们提出假说：抗阻运动改变血流切应力并下调内皮细胞miR-92a-3p表达，靶向HMOX1作用下游分子，预防CRT。本研究拟采用基因导入、基因干扰、运动干预动物模型等技术，从分子、细胞及动物水平探讨抗阻运动预防CRT的作用机制，揭示切应力、miR-92a-3p-HMOX1级联反应的生物学功能，为运动预防CRT提供理论依据。

导管相关性血栓（CRT）是中心静脉导管最严重并发症之一。血管内导管置入可引起血流动力学变化，促使CRT形成。研究表明，运动能预防CRT，但其分子机制尚未明确。miR-92a-3p在血栓组织中表达升高，而增加血流切应力能下调miR-92a-3p的表达。我们前期研究发现，抗阻运动能改变血流剪切力，降低内皮细胞miR-92a-3p表达，预防CRT。因此，本项目通过构建大鼠中心静脉导管模型，探讨抗阻运动调控miR-92a-3p预防大鼠CRT的作用。研究结果发现，抗阻运动可下调miR-92a-3p表达，提高HO1表达并抑制MAPKs/NF-κB信号通路激活，减少vWF的释放，进而修复氧化应激（OS）损伤；并且体外实验结果显示：层流剪切力可通过抑制miR-92a的表达，调控其下游KLF2/eNOS信号通路、抑制MAPKs/NF-κB信号通路激活，并减少MDA的表达、提高SOD酶活力，修复OS损伤。本研究阐明抗阻运动可引起血流剪切力的改变，修复OS损伤，预防CRT，为临床防治CRT提供新思路。