Chronic Intermittent Hypoxia Induces Atherosclerosis via Activation of Adipose Angiopoietin-like 4
Chronic Intermittent Hypoxia Induces Atherosclerosis via Activation of Adipose Angiopoietin-like 4
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DOI：
10.1164/rccm.201209-1688oc
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发表时间：
2013-07-15
影响因子：
24.7
通讯作者：
Polotsky, Vsevolod Y.
中科院分区：
文献类型：
--
作者：
Drager, Luciano F.;Yao, Qiaoling;Polotsky, Vsevolod Y.
基本原理：阻塞性睡眠呼吸暂停是血脂异常和动脉粥样硬化的一个危险因素，这已被归因于慢性间歇性缺氧（CIH）。间歇性低氧抑制脂蛋白清除的关键酶脂蛋白脂肪酶，并上调脂肪组织中的脂蛋白脂肪酶抑制剂血管生成素样4（Angptl 4）。Angptl 4上调在睡眠呼吸暂停中的作用和机制尚不清楚。目的：检测CIH是否通过缺氧诱导因子-1（HIF-1）增加脂肪Angptl 4诱导血脂异常和动脉粥样硬化。方法：ApoE（-/-）小鼠暴露于间歇性缺氧或空气4周，同时用Angptl 4中和抗体或载体治疗。测量和主要结果：在媒介物处理的小鼠中，缺氧增加脂肪Angptl 4水平，抑制脂肪脂蛋白脂肪酶，增加血浆甘油三酯和极低密度脂蛋白胆固醇的空腹水平，并增加动脉粥样硬化斑块的大小。CIH的作用可被抗体消除。在具有HIF-1 α基因敲除等位基因的种系杂合性的小鼠中未观察到低氧诱导的血浆空腹甘油三酯和脂肪Angptl 4的增加。脂肪组织中HIF-1 α的转基因过表达导致血脂异常和脂肪Angptl 4水平的增加。在培养的脂肪细胞中，HIF-1 α的组成型表达增加了Angptl 4水平，这被siRNA消除。最后，在接受减肥手术的肥胖患者中，夜间低氧血症的严重程度预测皮下脂肪组织中的Angptl 4水平。结论：HIF-1介导的脂肪Angptl 4增加和随后的脂蛋白脂酶活化可能有助于睡眠呼吸暂停患者的动脉粥样硬化。
Rationale: Obstructive sleep apnea is a risk factor for dyslipidemia and atherosclerosis, which have been attributed to chronic intermittent hypoxia (CIH). Intermittent hypoxia inhibits a key enzyme of lipoprotein clearance, lipoprotein lipase, and up-regulates a lipoprotein lipase inhibitor, angiopoietin-like 4 (Angptl4), in adipose tissue. The effects and mechanisms of Angptl4 up-regulation in sleep apnea are unknown.Objectives: To examine whether CIH induces dyslipidemia and atherosclerosis by increasing adipose Angptl4 via hypoxia-inducible factor-1 (HIF-1).Methods: ApoE(-/-) mice were exposed to intermittent hypoxia or air for 4 weeks while being treated with Angptl4-neutralizing antibody or vehicle.Measurements and Main Results: In vehicle-treated mice, hypoxia increased adipose Angptl4 levels, inhibited adipose lipoprotein lipase, increased fasting levels of plasma triglycerides and very low density lipoprotein cholesterol, and increased the size of atherosclerotic plaques. The effects of CIH were abolished by the antibody. Hypoxia-induced increases in plasma fasting triglycerides and adipose Angptl4 were not observed in mice with germline heterozygosity for a HIF-1 alpha knockout allele. Transgenic overexpression of HIF-1 alpha in adipose tissue led to dyslipidemia and increased levels of adipose Angptl4. In cultured adipocytes, constitutive expression of HIF-1 alpha increased Angptl4 levels, which was abolished by siRNA. Finally, in obese patients undergoing bariatric surgery, the severity of nocturnal hypoxemia predicted Angptl4 levels in subcutaneous adipose tissue.Conclusions: HIF-1-mediated increase in adipose Angptl4 and the ensuing lipoprotein lipase in activation may contribute to atherosclerosis in patients with sleep apnea.