PDE5/CXCL16介导炎性因子协同作用在颈动脉粥样硬化易损斑块中的机制研究

动脉粥样硬化（AS）是缺血性脑卒中的重要病因。我们在临床研究中发现在大动脉粥样硬化型脑卒中（LAA）患者中微栓子阳性组CXC趋化因子配体16（CXCL16）水平显著高于微栓子阴性组，高度提示血浆CXCL16水平与LAA脑梗死及斑块不稳定密切相关。我们又发现巨噬细胞分泌的炎性因子上调内皮细胞磷酸二酯酶-5（PDE5）和CXCL16的表达，可能促进斑块不稳定，但具体机制未明。我们提出假设：巨噬细胞分泌的炎性因子可通过相互正反馈调控导致其大量释放，炎性因子的协同作用通过正反馈促进PDE5使CXCL16表达增加，激活STAT3/NF-κB通路，引发内皮细胞增殖、迁徙及成管，最终影响动脉粥样斑块稳定性。拟通过临床标本分析各因素相关性；流式细胞分析炎症因子正反馈调控；质粒转染等验证炎症因子对PDE5/CXCL16的正反馈调控；动物实验体内验证。为有效干预颈AS提供新策略。

Atherosclerosis (AS) is an important cause of ischemic stroke. In the clinical study we found an elevation of serum CXCL16 level correlated well with microembolic signals in acute stroke patients with carotid artery stenosis. It revealed that an elevation of serum CXCL16 level might contribute to plaque destabilization. We also found the inflammatory cytokines secreting by macrophage increased the expressions of phosphodiesterase 5 (PDE5) and CXCL16 in endothelial cells, but the exact mechanism is unclear. We suppose that the inflammatory cytokines produced by infiltrating macrophages could up-regulate their own production through positive feedback to each other. The synergy of inflammatory cytokines increase PDE5 and CXCL16 expressing, then promote activating STAT3/NF-κB pathway and cell proliferation, migration and angiogenesis, this ultimately affect plaque stability. In order to testify our hypothesis, we will analyze clinical samples to verify the relationship among different factors studied; investigate the positive feedback of cytokines produced by macrophages by flow cytometry analysis; the synergistic effect of cytokines on promoting PDE5 /CXCL16 pathway. Animal experiments will be done to confirm the hypothesis in vivo. This project will provide new and effective strategies to intervene the formation and stability of carotid atherosclerosis.