震荡流活化TLR2-TAK1-IKK1-3致支架内再狭窄的机制研究

血管震荡流引起内皮剪切力（ESS）梯度增大致斑块破裂或糜烂及血栓形成是急性冠状动脉综合征的主要病因。Toll样受体2 （TLR2）信号通路参与糜烂和易损斑块的发展，但其与支架内再狭窄（ISR）的关系不明。TAK1是TLR2通路的关键分子。研究表明药物洗脱支架术后分支开口ISR率极高，但机制不清楚。我们前期研究发现分支开口显著增大的ESS梯度与ISR密切相关。我们的预实验发现震荡流活化TLR2下游的核因子（NF）-kB激酶1-3抑制剂（IKK1-3）。据此，我们提出科学假设：震荡流通过激活TLR2-TAK1-IKK1-3导致ISR。为验证这一假设，我们拟采用内皮细胞、动物及冠心病患者，运用平行板流动腔、原子力显微镜、血管腔内成像等技术，从细胞和整体水平研究ESS梯度增大和震荡流促进ISR的作用及机制，从而为寻找防治ISR的新靶点提供理论及实验依据。

Abnormal endothelial shear stress (ESS) caused by oscillatory flow resulting in plaque rupture or erosion and thrombosis formation is one of the underlying mechanism of acute coronary syndrome (ACS) with high mortality. Toll like receptor2 (TLR2) is involved in development of plaque erosive and vulnerable plaques, whereas little is known about its relationship with ISR. TAK1 is one of key molecules in the TLR2 pathway. The mechanism of high rate of restenosis (ISR) at the side branch (SB) ostium after drug eluting stents implantation was still unclear. Our previous studies reveal abnormal ESS distribution of SB was relevant to ISR. A pilot study found abnormal ESS with oscillatory blood flow induced TLR2-inhibitor of nuclear factor kappa-B kinase (IKK1-3), thus leading to enhanced JNK, p38 and activator protein (AP)-1. Therefore, we hypothesized oscillatory flow induced ISR via TLR2-TAK1-IKK1-3 pathway. To verify the hypothesis, we proposed to use gene expression vector, parallel plate chamber, RT-qPCR , immunoblotting, electron microscope, atomic force microscope as well as intravascular imaging techniques, in cultured endothelial cells, animals and patients with coronary artery diseases. Our results will provide the theoretical and experimental evidences and novel targets for the treatment of ISR.