OCT研究PGE2-EP4通路调控的透明质酸代谢在斑块侵蚀形成中的作用和机制

Atherosclerotic plaque erosion (PE) is believed to be important pathological mechanism responsible for acute coronary syndrome (ACS). However, data on the mechanism of plaque erosion is crucial limited. Recently, our group for the first time in the world, reported that plaque erosion can be diagnosed by intravascular optical coherence tomography (OCT) in vivo. Pathologically, plaque erosion is characterized by absence of endothelial cells and hyaluronan (HA) accumulation, excessive smooth muscle cells proliferation, at the interface of eroded area. HA has involved in regulation of proliferation and apoptosis via interacting with its multiple receptors. We therefore postulate that metabolic disorder of HA play a central role in development of PE. Furthermore, this metabolism disorder may depend on the activation of PGE2/EP4 in the inflammatory circumstance. Our previous study showed that telomere binding-protein TPP1 can directly regulated the process of aging and apoptosis. It is unknown whether HA can induce endothelial apoptosis and smooth muscle cell immature via impacting on TPP1 expression. In this study, we aim to investigate the impact of hyaluronan regulated by PGE2/EP4 on the development of PE in vitro as well as in vivo. For the first time, we will illustrate the underlying mechanism of plaque erosion using multiple imaging modality including OCT and VH-IVUS combining with gene transection and knockout, immunofluorescence, and PCR. As to provide the new evidence and the new target for accurate treatment of ACS.

斑块侵蚀(PE)是急性冠脉综合征(ACS)的重要病理机制。然而目前对PE的认识非常有限。课题组在国际上首次证实光学相干断层成像(OCT)可在体识别PE。既往研究显示发生PE的内皮下透明质酸(HA)聚集、平滑肌细胞(SMC)增生。而HA通过不同受体介导多种生物学过程(细胞增生与凋亡)。因此，我们推测HA代谢异常可能是形成PE的核心环节，而前者依赖于PGE2/EP4通路的参与。我们前期证实，端粒保护蛋白TPP1可调控内皮细胞老化和凋亡。HA能否通过不同受体调控SMC和内皮细胞TPP1表达水平，促进SMC增殖同时介导内皮细胞凋亡，从而影响PE的形成？这一机制尚未明确。本课题将联合OCT及虚拟组织学影像技术，通过基因敲除与转染，免疫荧光，Western和PCR等方法，首次从细胞到整体水平探讨PGE2/EP4调控的HA代谢障碍对PE形成的作用和机制。为精准治疗ACS提供理论依据和干预的新靶点。

斑块侵蚀(PE)是导致急性冠脉综合征(ACS)的重要病理机制。然而目前对PE的认识非常有限。课题组在国际上首次证实光学相干断层成像(OCT)可在体识别PE。既往研究显示PE病变内皮下透明质酸(HA)聚集、平滑肌细胞(SMC)增生。而HA通过不同受体介导多种生物学过程(细胞增殖与凋亡)。因此，我们推测HA代谢异常可能是形成PE的核心环节，而前者依赖于PGE2/EP4通路的参与。我们通过体外实验证实PGE2/EP4通路可以促进SMC迁移，上调SMC透明质酸合成酶，进而促进HA的合成。HA的功能与其分子量大小密切相关，我们证实低分子量的HA通过RHAMM/AKT/ERK通路诱导内皮细胞凋亡，同时伴有线粒体功能紊乱和氧化应激失衡。目前对PE的识别主要依赖于有创的OCT技术，如何实现在体无创诊断PE是当前心血管领域的一大难题。我们选取人外周血白细胞作为研究对象，对PE和斑块破裂（PR）患者透明质酸相关生物标志物的表达水平进行系统分析，发现HAS-1、CD44 V1、CD44 V6有望作为鉴别PE和PR的潜在生物标志物，CD44 V1和V6两基因联合分析可以提高对PE诊断的敏感性和特异性；同时收集PE和PR患者外周血血浆样本，通过microRNA芯片高通量测序发现PE和PR两组人群中存在34个有差异的miRNAs，后续人群验证发现PE患者循环miR-3667-3p的表达水平显著升高，对PE的诊断具有预测价值。本课题围绕PE开展了一系列基础和临床研究，通过分子实验技术证实PGE2/EP4信号通路调控HA代谢紊乱对PE形成的作用及机制，同时联合OCT和组学分析寻找预测PE病变的敏感而特异的生物标志物指标，构建PE预测模型，为PE无创诊断提供理论依据。