雌雄激素协同作用对内皮细胞IL-6/gp130信号通路的抑制效应及其抗动脉粥样硬化的机制研究

Atherosclerosis (AS) is a chronic inflammatory response disorder. IL-6/gp130 signaling pathway stimulates the development of AS. Therefore, inhibition of the activity of IL-6/gp130 signaling pathway becomes a hot topic in the field of prevention and treatment of AS. Recently, the theory of the nerve-endocrine-inflammation network provides a new explanation for the pathophysiologic process of coronary heart disease (CHD). According to this theory, the applicant’s previous research showed that the balance of the serum estradiol and testosterone ratio was broken in postmenopausal women with CHD, and an imbalanced estradiol and testosterone ratio showed a strong association with hsCRP. This indicates that the imbalanced estradiol and testosterone ratio can upregulate the inflammatory factors which may be a crucial cause of the development of AS. Furthermore, in HUVECs, estradiol combined with testosterone can significantly downregulate the expression of gp130, which indicates that the synergistic effect of estradiol and testosterone can reduce the inflammation through the reduction of the level of gp130. This research will be based on the applicant’s present results, and will be followed by discussion of the inhibition of the synergistic effect of estradiol and testosterone in the IL-6/gp130 signaling pathway. Finally, the focus will be on determining the molecular mechanism of the anti-atherosclerotic effect, which would provide new ideas and a target for AS treatment.

动脉粥样硬化（AS）是一种多因素导致的慢性炎症疾病。IL-6/gp130信号通路的激活对AS的发生发展具有促进作用。因此，抑制该信号通路的活化是AS防治研究的热点。近年来，神经-内分泌-炎症网络学说为冠心病的病理生理过程做出了新的解释，根据此学说，申请者前期研究表明，绝经后女性冠心病患者体内雌/雄激素比例会发生失衡，血清hsCRP水平也与雌雄激素比例呈显著负相关，提示雌雄激素比例失衡会引起炎性因子表达上调是促使AS进行性发展的重要因素。进一步细胞学研究发现，在HUVECs中给予雌雄激素联合给药可明显下调gp130蛋白的水平，提示雌雄激素协同作用可通过抑制gp130的水平发挥抗炎效应。本研究拟在现有研究基础上深入探讨雌雄激素协同作用对IL-6/gp130信号通路的抑制及其抗动脉粥样硬化的分子机制，为冠心病的防治提供新思路；通过gp130的检测，提示gp130可以作为启动AS进程的新靶标。

动脉粥样硬化是冠心病（CAD）的病理基础，炎症可诱发血管内皮损伤，促进动脉粥样硬化的发生。而白细胞介素6（IL-6）是重要的促炎因子，同时也是CAD的独立危险因素。IL-6可通过gp130蛋白作用于血管内皮细胞，促进趋化因子和粘附分子的表达，从而诱导单核细胞和巨噬细胞等炎症细胞向血管内膜趋化、粘附，进而吞噬血管内膜中沉淀的脂质形成泡沫细胞，最终诱发动脉粥样斑块的形成。因而，抑制IL-6/gp130信号通路的活化已成为动脉粥样硬化预防与治疗的研究热点。此外，CAD的发生具有一定的年龄和性别差异，提示性激素与CAD的发病机制密切相关。前期研究表明，性激素可以通过其受体调节gp130蛋白的水平和功能，阻断IL-6下游的信号传导，抑制相应的生物学效应，然而，关于性激素调节IL-6/gp130信号通路在动脉粥样硬化的作用效应尚不明确。因此，本研究将激素水平和炎症因子联系起来，从血清学、细胞学、动物学三个水平探讨睾酮和雌二醇协同对IL-6/gp130信号通路的抑制效应及其抗动脉粥样硬化的分子机制。研究数据表明，男性CAD患者血清sgp130浓度随着雌二醇和睾酮/雌二醇比值的降低而显著下降。在原代人脐静脉内皮细胞水平发现，雌雄激素协同抑制IL-6/gp130/STAT3信号通路，从而抑制炎症反应，对血管内皮细胞起保护效应。在ApoE-/-小鼠和ApoE-/-GP130-/-小鼠水平中，证实雌雄激素协同作用通过调节gp130蛋白及其下游信号通路发挥抗动脉粥硬化作用。最终证实，雌雄激素协同作用通过下调gp130蛋白水平并调节其下游信号通路的活化状态，抑制IL-6诱导的血管内皮的炎症反应，保护血管内膜免受损伤，从而发挥抗动脉粥样硬化的作用，为CAD的预防与治疗提供新思路。