流行病学显示慢性间歇性低氧（CIH）增加动脉粥样硬化（AS）发生，但机制不清。低氧诱导因子1（HIF1）是介导细胞低氧适应性反应的关键核转录因子。最近研究显示，低氧可促进巨噬细胞炎症及泡沫细胞形成。我们前期发现，激活巨噬细胞HIF1 a可促进巨噬细胞炎症及AS形成，进一步研究发现，低氧及持续激活HIF1a均可增加巨噬细胞NLRP3 mRNA和蛋白表达及炎症小体活化，启动子序列分析提示NLRP3启动子上存在HIF1a结合位点。据此我们提出假说：CIH可能通过激活HIF1a及其靶基因NLRP3表达，促进巨噬细胞炎症小体活化，从而加速AS发生发展，抑制HIF1a或NLRP3可延缓CIH时AS发生发展。本研究将利用巨噬细胞HIF1a过表达/敲除小鼠及特异性抑制剂来研究HIF1a-NLRP3炎症小体通路在CIH加剧AS进程中的作用及机制。研究将有助于阐明CIH促进AS的新机制并为治疗提供潜在靶点。

Chronic intermittent hypoxia (CIH) promotes atherosclerosis (AS) with unknown mechanisms. Hypoxia-inducible factor 1 is a transcription factor critical for the cellular adaptive response to hypoxia. Recent studies showed that hypoxia could exacerbate macrophage inflammation and foam cell formation, a key characteristic of AS. Our preliminary data demonstrated constitutive HIF1a activation by vhl disruption in macrophages could enhance macrophage inflammation and accelerate AS in apoE-null mice. Further studies showed that hypoxia or constitutive HIF1a activation could activate NLRP3-dependent inflammasome activation. Promoter analysis showed that NLRP3 promoter region contains putative hypoxia response elements (HREs), indicating that NLPR3 might be HIF1a direct target gene. Therefore, we hypothesize that CIH accelerates AS via activation of HIF1a and its target gene NLRP3. We will identify the role of macrophage HIF1a-NLRP3 inflammasome axis in CIH-accelerated AS in apoE-null mice with macrophage-specific HIF1a disruption or overexpression in vitro and in vivo, and evaluate the suppressive effects of HIF1a or NLRP3 inhibitor on CIH-induced AS. Our study will clarify the novel mechanism for CIH-promoted AS and provide potential therapeutic targets for AS.