Xue Jin, Zhou Dan, Poulsen Orit, Imamura Toshihiro, Hsiao Yu-Hsin, Smith Travis H, Malhotra Atul, Dorrestein Pieter, Knight Rob, Haddad Gabriel G
Departments of 1 Pediatrics.
2 Internal Medicine, and.
Am J Respir Cell Mol Biol. 2017 Nov;57(5):581-588. doi: 10.1165/rcmb.2017-0086OC.
Obstructive sleep apnea (OSA) is a common disorder characterized by intermittent hypoxia and hypercapnia (IHC) during sleep. OSA has been shown to be a risk factor for atherosclerosis, but the relation of IHC to the induction or progression of atherosclerosis is not well understood. To dissect the mechanisms involved, we compared atherosclerotic lesion formation in two mouse models, i.e., apolipoprotein E (ApoE) and low density lipoprotein receptor (Ldlr)-deficient mice, with or without IHC exposure. Ten-week-old ApoE or Ldlr mice were fed a high-fat diet for 4 or 8 weeks while being exposed to IHC for 10 hours/day or room air (RA) for 24 hours/day. En face lesions of the aorta, aortic arch, and pulmonary artery (PA) were examined. Moreover, 3,3-dimethyl-1-butanol (DMB), an inhibitor of microbial trimethylamine (TMA) production, was used to determine the contribution of TMA-oxide (TMAO) to IHC-induced atherosclerosis. Eight weeks of IHC exposure expedited the formation of atherosclerosis in both the PA and aortic arch of ApoE mice, but only in the PA of Ldlr mice (ApoE PA 8 wk, IHC 35.4 ± 1.9% versus RA 8.0 ± 2.8%, P < 0.01). The atherosclerotic lesions evolved faster and to a more severe extent in ApoE mice as compared with Ldlr mice (PA IHC 8 wk, ApoE 35.4 ± 1.9% versus Ldlr 8.2 ± 1.5%, P < 0.01). DMB significantly attenuated but did not totally eliminate IHC-induced PA atherosclerosis. Our findings suggest that IHC, a hallmark of OSA, accelerates the progression of atherosclerosis in the aorta and especially in the PA. This process is partly inhibited by DMB, demonstrating that microbial metabolites may serve as therapeutic targets for OSA-induced atherosclerosis.
阻塞性睡眠呼吸暂停（OSA）是一种常见疾病，其特征为睡眠期间间歇性缺氧和高碳酸血症（IHC）。OSA已被证明是动脉粥样硬化的一个危险因素，但IHC与动脉粥样硬化的诱导或进展之间的关系尚未完全明确。为了剖析其中涉及的机制，我们比较了两种小鼠模型（即载脂蛋白E（ApoE）和低密度脂蛋白受体（Ldlr）缺陷小鼠）在有或无IHC暴露情况下动脉粥样硬化病变的形成情况。10周龄的ApoE或Ldlr小鼠喂食高脂饮食4周或8周，同时每天暴露于IHC 10小时或每天暴露于室内空气（RA）24小时。检查主动脉、主动脉弓和肺动脉（PA）的正面病变。此外，使用微生物三甲胺（TMA）产生的抑制剂3,3 - 二甲基 - 1 - 丁醇（DMB）来确定氧化三甲胺（TMAO）对IHC诱导的动脉粥样硬化的作用。暴露于IHC 8周加速了ApoE小鼠PA和主动脉弓中动脉粥样硬化的形成，但仅在Ldlr小鼠的PA中出现（ApoE PA 8周，IHC为35.4±1.9%，而RA为8.0±2.8%，P < 0.01）。与Ldlr小鼠相比，ApoE小鼠的动脉粥样硬化病变发展更快且程度更严重（PA IHC 8周，ApoE为35.4±1.9%，而Ldlr为8.2±1.5%，P < 0.01）。DMB显著减轻但并未完全消除IHC诱导的PA动脉粥样硬化。我们的研究结果表明，IHC作为OSA的一个标志，加速了主动脉尤其是PA中动脉粥样硬化的进展。这一过程部分受到DMB的抑制，表明微生物代谢产物可能成为OSA诱导的动脉粥样硬化的治疗靶点。
