间断性缺氧介导激活的ROS--HIF-1α通路在主动脉夹层形成中的分子机制研究

Aortic dissection (AD) is a life-threatening cardiovascular disease with highin-hospital mortality. Obstructive sleep apnea (OSA), due to its high morbidity,makes it becoming one of the most important risk factors of many cardiovasculardiseases. In addition OSA has been increasingly recognized as an independent riskfactor for AD and it is strongly associated with the extent of intermittenthypoxia and re-oxygenation (IHR). IHR can increase reactive oxygen species (ROS)production, which in turn stabilizes hypoxia inducible factor 1α (HIF-1α), a keytranscription factor, which participates in the occurrence and progression ofnumerous cardiovascular diseases by regulating the expression of multiplesignaling molecules. Consistent with the previous reports our preliminary datareveal that patients with AD present a significant higher prevalence of OSA andthe expression of oxidative stress markers and HIF-1α in their aortic tissuesincreased significantly compared to the respective controls. Furthermore, HIF-1α can up-regulate the expression of matrix metalloproteinases (MMPs) and their activity as well. Thus, we hypothesize that OSA induced IHR can promote theoccurrence and progression of AD via a ROS- HIF-1α-MMPs pathway. In order toelucidate the underlying mechanisms we will apply in the current proposal in vitrocell experiments, in vivo Ang II infused AD animal model . We expect that these studies will provide novel insights into themechanisms by which OSA induced ROS and HIF-1α contribute to the occurrence and progression of AD and may allow the design of cell type specific targetedtherapies.

主动脉夹层（AD）是一种致命性的心血管疾病。阻塞性呼吸睡眠暂停综合征（OSA）是AD的独立危险因素，并且与间歇性低氧及复氧（IHR）程度密切相关。IHR介导氧化应激激活缺氧诱导因子1α（HIF-1α），调控多种信号分子的转录翻译，参与多种心血管疾病的发生发展。同文献报道一致，我们前期发现AD患者合并OSA的比例显著高于非OSA对照组，其主动脉组织中氧化应激标志蛋白及HIF-1α表达也较对照组明显升高。我们提出假设，OSA引起的IHR通过激活氧化应激介导上调HIF-1α，进而上调并活化基质金属蛋白酶(MMPs)从而参与AD的发生发展。本实验利用间断缺氧诱导的OSA模型及血管紧张素Ⅱ (Ang Ⅱ)微泵灌注的AD模型，通过动物实验，细胞实验研究氧化应激及HIF-1α在OSA参与AD的作用及机制，并通过相关通路抑制剂探索可能的治疗靶点，为AD的防治提供新思路。

主动脉夹层（AD）是一种致命性的心血管疾病。阻塞性呼吸睡眠暂停综合征（OSA）是AD 的独立危险因素，并且与间歇性低氧及复氧（IHR）程度密切相关。IHR介导氧化应激激活缺氧诱导因子1α（HIF-1α），调控多种信号分子的转录翻译，参与多种心血管疾病的发生发展。 同文献报道一致，我们前期发现AD患者合并OSA的比例显著高于非OSA对照组，其主动脉组织中 氧化应激标志蛋白及HIF-1α表达也较对照组明显升高。我们提出假设，OSA引起的IHR通过激 活氧化应激介导上调HIF-1α，进而上调并活化基质金属蛋白酶(MMPs)从而参与AD的发生发展 。本实验利用间断缺氧诱导的OSA模型及血管紧张素Ⅱ微泵灌注的AD动物模型，通过动物实验，细胞实验研究氧化应激及HIF-1α在OSA参与AD的作用及机制。我们将小鼠暴露于IH（20.9% O2/8% O2 FiO2，每小时30次，每次低氧20s）中4周。在Ang II (2500 ng/min/kg)或盐水微泵14天后，收集标本并进行α-SMA免疫组织化学和弹性蛋白染色。组织学检查显示Ang组14天后管腔明显扩大，中膜破坏，外膜明显增厚。发生率及死亡率都明显升高。IH加重了这些变化。并通过体外细胞实验发现，IH条件下产生大量活性氧ROS通过PI3K-AKT-FRAP通路诱导HIF-1α的产生。随后,稳定HIF-1α把进入细胞核,连同其他转录因子,如HIF-1β,激活下游的基因转录,包括VEGF和MMP-2/9在ECM重塑中发挥重要作用。分泌的MMPs导致主动脉ECM成分，如弹性蛋白和胶原，降解，从而促进AD的发生和进展。在我们OSAS-AD小鼠模型中，由新型小分子抑制剂药物KC7F2抑制HIF-1α可以改善IH条件下诱导的AD的发生，并可能为OSA合并AD 患者提供新的预防和治疗思路。

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