Department of Pediatrics, The University of Chicago, Chicago, IL 60637, USA.
Am J Respir Crit Care Med. 2011 Jul 1;184(1):124-31. doi: 10.1164/rccm.201012-2039OC. Epub 2011 Apr 14.
Obstructive sleep apnea, which is characterized by intermittent hypoxia (IH) during sleep, has emerged as an independent risk factor for cardiovascular disease, including atherosclerosis. Leukotriene B4 (LTB4) production is increased in patients with obstructive sleep apnea and negatively correlates to hypoxic levels during sleep, with continuous positive airway pressure therapy decreasing LTB4 production.
Determine the potential role of LTB4 in IH-induced atherosclerosis in a monocyte cellular model and a murine model.
THP-1 cells were exposed to IH for 3, 6, 24, and 48 hours. Macrophage transformation and foam cell formation were assessed after IH exposures. Apolipopotein E (ApoE)(-/-) or BLT1(-/-)/ApoE(-/-) mice were fed an atherogenic diet and exposed to IH (alternating 21% and 5.7% O(2) from 7 am to 7 PM each day) for 10 weeks. Atherosclerotic lesion formation in en face aorta was examined by oil red O staining.
IH increased production of LTB4 and the expression of 5-lipoxygenase and leukotriene A4 hydrolase, the key enzymes for producing LTB4. IH was associated with transformation of monocytes to activated macrophages, as evidenced by increased expression of CD14 and CD68. In addition, IH exposures promoted increased cellular cholesterol accumulation and foam cell formation. The LTB4 receptor 1 (BLT1) antagonist U-75302 markedly attenuated IH-induced changes. Furthermore, IH promoted atherosclerotic lesion formation in ApoE(-/-) mice. IH-induced lesion formation was markedly attenuated in BLT1(-/-)/ApoE(-/-) mice.
BLT1-dependent pathways underlie IH-induced atherogenesis, and may become a potential novel therapeutic target for obstructive sleep apnea-associated cardiovascular disease.
阻塞性睡眠呼吸暂停（obstructive sleep apnea）以睡眠期间间歇性缺氧（intermittent hypoxia，IH）为特征，它已成为心血管疾病（包括动脉粥样硬化）的独立危险因素。患有阻塞性睡眠呼吸暂停的患者白三烯 B4（leukotriene B4，LTB4）的产生增加，并且与睡眠期间的缺氧水平呈负相关，持续气道正压通气治疗可降低 LTB4 的产生。
在单核细胞细胞模型和小鼠模型中确定 LTB4 在 IH 诱导的动脉粥样硬化中的潜在作用。
将 THP-1 细胞暴露于 IH 中 3、6、24 和 48 小时。在 IH 暴露后评估巨噬细胞转化和泡沫细胞形成。载脂蛋白 E（apolipoprotein E，ApoE）（-/-）或 BLT1（-/-）/ApoE（-/-）小鼠喂食动脉粥样硬化饮食，并每天从上午 7 点到晚上 7 点暴露于 IH（交替 21%和 5.7%O2）10 周。用油红 O 染色法检查主动脉正面的动脉粥样硬化病变形成。
IH 增加了 LTB4 的产生以及 5-脂氧合酶和白三烯 A4 水解酶的表达，这两种酶是产生 LTB4 的关键酶。IH 与单核细胞向活化的巨噬细胞转化有关，这表现为 CD14 和 CD68 的表达增加。此外，IH 暴露促进了细胞胆固醇积累和泡沫细胞形成的增加。LTB4 受体 1（BLT1）拮抗剂 U-75302 明显减弱了 IH 引起的变化。此外，IH 促进了 ApoE（-/-）小鼠的动脉粥样硬化病变形成。BLT1（-/-）/ApoE（-/-）小鼠中 IH 诱导的病变形成明显减弱。
BLT1 依赖性途径是 IH 诱导动脉粥样硬化形成的基础，可能成为阻塞性睡眠呼吸暂停相关心血管疾病的潜在新的治疗靶点。
