缺氧诱导因子2α基因敲除对小鼠动脉粥样硬化发生的影响

Effect of hypoxia inducible factor 2α gene knockout on atherosclerosis in mice

目的明确缺氧诱导因子(hypoxia inducible factor,HIF)-2α对动脉粥样硬化病变的影响。方法引进获得HIF-2α基因LoxP标记小鼠和Mx-Cre转基因小鼠,利用Cre/LoxP系统建立条件性HIF-2α基因敲除的小鼠模型,同时以Mx-Cre阴性的野生型小鼠和ApoE基因缺陷小鼠为对照,高脂饲料喂养8周后对小鼠主动脉进行HE染色,观察动脉粥样硬化病变形成情况。结果 HIF-2α-LoxP标记小鼠和Mx-Cre转基因小鼠交配后,经过两次传代和基因型鉴定筛选,获得Mx-Cre阳性且HIF-2α纯合LoxP标记小鼠,采用聚肌胞腹腔注射后可成功建立HIF-2α基因敲除小鼠模型。高脂喂养8周后,ApoE基因缺陷小鼠主动脉呈动脉粥样硬化样改变,野生型小鼠可见轻度内膜增生,而HIF-2α基因敲除小鼠主动脉内膜未见增生。结论 HIF-2α基因敲除可抑制小鼠动脉粥样硬化病变的形成,提示针对HIF-2α的基因治疗可能是动脉粥样硬化防治策略的新方向。

Objective To study the effect of hypoxia inducible factor 2α （HIF-2α） gene knockout on atherosclerosis in mice. Methods LoxP-labeled HIF-2αmice and Mx-Cre-labeled transgenic mice were enrolled in this study. A mouse model of conditional HIF-2α gene knockout was established with the Cre/LoxP system. Mx-Cre negative wild-type mice and ApoE gene deletion （ApoE-/-） mice served as controls. Atherosclerotic lesions of aorta were observed in the animals with HE staining 8 weeks after being fed with a high fat diet. Results Mx-Cre positive LoxP-labeled HIF-2α mice and Mx-Cre-labeled transgenic mice were produced after they mated by two passages and genotype identification. The mouse model of conditional HIF-2α gene knockout was successfully established by intra-abdominal injection with polycytidilic acid. Eight weeks after the animals were fed with a high fat diet, atherosclerotic lesions and mild intimal hyperplasia were detected in ApoE-/- mice and wild-type mice, respectively. However, no intimal hyperplasia was detected in HIF-2α-/- mice. Conclusion HIF-2α gene knockout can inhibit the formation of atherosclerotic lesions in mice, indicating that gene therapy for HIF-2α is a novel strategy for the prevention and treatment of atherosclerosis.