HDAC5/HSP90/HIF-1α信号介导Th17细胞分化在肺动脉高压中的作用研究

Hypoxia and inflammation play significant roles in developing pulmonary arterial hypertension (PAH). The anomalous differentiation of Th17 cells has a close relationship with PAH. Recent studies revealed that hypoxia could up-regulate the expression of hypoxia-inducible factor-1α (HIF-1α), heat shock protein (HSP90) played an important role in molecular chaperone effect, which maintained the stability of HIF-1α, and histone deacetylase (HDACs) family protein probably had effects in regulating HSP90. Our previous studies found out that hypoxia stimulus could up-regulate Th17 cells differentiation and its HIF-1α expression in vitro. Secondly, the HIF-1α inhibitor could down-regulate Th17 cells expression in splenocytes of hypoxia-induced mice PAH model. Thirdly, hypoxia stimulus could facilitate HDAC5 mRNA expression of lymphocyte cells in vivo and in vitro. Finally, HDAC5 expression was associated with HSP90 acetylation level In vitro . We inferred that besides strengthening HIF-1α expression, hypoxia stimulus could regulate HDAC5 expression, which could up-regulate HSP90. This resulted in maintaining HIF-1α stability, which could further promote CD4+ native T cells to be differentiated into Th17 cells. Our study will focus on hypoxia stimulus regulating Th17 cells differentiation, which can influence PAH development by signaling pathway of HDAC5/HSP90/HIF-1α through in vivo and in vitro experiments.

低氧状态广泛存在于肺动脉高压(PAH)发展过程中，Th17细胞分化异常与PAH关系密切。最近发现，低氧能上调细胞缺氧诱导因子1α(HIF-1α)表达，热休克蛋白90(HSP90)发挥分子伴侣作用维持HIF-1α稳定，组蛋白去乙酰化酶（HDACs)有可能对HSP90具有功能调节作用。申请者前期发现，低氧刺激能增强体外Th17细胞分化及HIF-1α表达；HIF-1α抑制剂能下调PAH模型脾细胞中Th17细胞表达；低氧刺激能促进体内、体外淋巴细胞HDAC5 mRNA表达；体外HDAC5表达与HSP90乙酰化水平相关 。由此推测：低氧刺激除能直接增强细胞HIF-1α表达外，还可能通过调节HDAC5表达，上调HSP90功能，维持HIF-1α稳定性途径促进CD4+原始T细胞向Th17细胞分化。本项目将研究低氧刺激经HDAC5/HSP90/HIF-1信号途径调节Th17细胞分化影响PAH发展的作用。

低氧状态广泛存在于肺动脉高压(PAH)发展过程中。最近发现，低氧能上调细胞缺氧诱导因子1α(HIF-1α)表达，热休克蛋白90(HSP90)发挥分子伴侣作用维持HIF-1α稳定，组蛋白去乙酰化酶（HDACs)有可能对HSP90具有功能调节作用。申请者前期发现，低氧刺激能增强体外Th17细胞分化及HIF-1α表达；HIF-1α抑制剂能下调PAH模型脾细胞中Th17细胞表达；低氧刺激能促进体内、体外淋巴细胞HDAC5 mRNA表达；体外HDAC5表达与HSP90乙酰化水平相关。由此推测：低氧刺激除能直接增强细胞HIF-1α表达外，还可能通过调节HDAC5表达，上调HSP90功能，维持HIF-1α稳定性途径促进CD4+原始T细胞向Th17细胞分化。本项目将研究低氧刺激经HDAC5/HSP90/HIF-1信号途径调节SMC细胞分化影响PAH发展的作用。在研究推进过程中，项目组还发现，1：缺氧通过影响自噬信号通路促进了细胞存活并增加了HDAC5-HSP90的表达；2：HDAC5表达抑制后影响了缺氧对细胞的增殖等作用；3：HSP90表达抑制后影响了缺氧对细胞的增殖等作用；4：HDAC5影响了缺氧诱导因子HIF1a与HSP90的相互作用并进一步影响了HIF1a的稳定性；5：体内实验发现HDAC5抑制后对PAH大鼠模型肺部病损具有改善作用。