Molecular biomarkers of vascular dysfunction in obstructive sleep apnea.
Molecular biomarkers of vascular dysfunction in obstructive sleep apnea.
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DOI：
10.1371/journal.pone.0070559
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Malhotra A
中科院分区：
文献类型：
--
作者：
Kaczmarek E;Bakker JP;Clarke DN;Csizmadia E;Kocher O;Veves A;Tecilazich F;O'Donnell CP;Ferran C;Malhotra A
未经治疗和长期持续的阻塞性睡眠呼吸暂停（OSA）可能导致重要的血管异常，包括内皮细胞（EC）功能障碍，高血压和动脉粥样硬化。我们观察了OSA患者微循环反应性和内皮依赖性一氧化氮释放之间的相关性。因此，我们假设OSA影响（微）血管系统，我们的目的是确定OSA的血管基因靶点，这些靶点可能作为疾病严重程度和血管风险的可靠生物标志物。使用定量RT-PCR，我们评估了基因表达在皮肤活检的OSA患者，小鼠动脉瘤动物暴露于4周间歇性缺氧（IH;氧去饱和和复氧的快速振荡），和人真皮微血管（HMVEC）和冠状动脉内皮细胞（HCAEC）培养下IH。我们证明了内皮型一氧化氮合酶（eNOS）、肿瘤坏死因子-α诱导蛋白3（TNFAIP 3; A20）、缺氧诱导因子1 α（HIF-1α？和血管内皮生长因子（VEGF）的表达，与轻度低氧血症的OSA患者（SaO 2 75%-90%）相比，从具有严重夜间低氧血症（最低饱和氧水平[SaO 2]<75%）的OSA患者获得的皮肤活检组织中，与对照受试者相比，血管细胞粘附分子1（VCAM-1）的表达显著上调。暴露于IH的小鼠睾丸中的基因表达谱显示eNOS和VEGF显著上调。在OSA的体外模型中，IH增加了HMVEC中A20的表达，降低了eNOS和HIF-1α的表达，而增加了HCAEC中A20、VCAM-1和HIF-1α的表达，表明培养的EC对IH应激的反应不同。我们的结论是，基因表达谱在OSA患者的皮肤可能与疾病的严重程度，如果通过进一步的研究验证，可能预测血管风险OSA患者。
Untreated and long-lasting obstructive sleep apnea (OSA) may lead to important vascular abnormalities, including endothelial cell (EC) dysfunction, hypertension, and atherosclerosis. We observed a correlation between microcirculatory reactivity and endothelium-dependent release of nitric oxide in OSA patients. Therefore, we hypothesized that OSA affects (micro)vasculature and we aimed to identify vascular gene targets of OSA that could possibly serve as reliable biomarkers of severity of the disease and possibly of vascular risk. Using quantitative RT-PCR, we evaluated gene expression in skin biopsies of OSA patients, mouse aortas from animals exposed to 4-week intermittent hypoxia (IH; rapid oscillations in oxygen desaturation and reoxygenation), and human dermal microvascular (HMVEC) and coronary artery endothelial cells (HCAEC) cultured under IH. We demonstrate a significant upregulation of endothelial nitric oxide synthase (eNOS), tumor necrosis factor-alpha-induced protein 3 (TNFAIP3; A20), hypoxia-inducible factor 1 alpha (HIF-1α?? and vascular endothelial growth factor (VEGF) expression in skin biopsies obtained from OSA patients with severe nocturnal hypoxemia (nadir saturated oxygen levels [SaO2]<75%) compared to mildly hypoxemic OSA patients (SaO2 75%–90%) and a significant upregulation of vascular cell adhesion molecule 1 (VCAM-1) expression compared to control subjects. Gene expression profile in aortas of mice exposed to IH demonstrated a significant upregulation of eNOS and VEGF. In an in vitro model of OSA, IH increased expression of A20 and decreased eNOS and HIF-1α expression in HMVEC, while increased A20, VCAM-1 and HIF-1αexpression in HCAEC, indicating that EC in culture originating from distinct vascular beds respond differently to IH stress. We conclude that gene expression profiles in skin of OSA patients may correlate with disease severity and, if validated by further studies, could possibly predict vascular risk in OSA patients.
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DOI：
10.1152/ajprenal.00006.2004
发表时间：
2004-09-01
影响因子：
4.2
作者：
Chu, SY;Bohlen, HG
通讯作者：
Bohlen, HG
影响因子：
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作者：
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DOI：
10.1111/j.1365-2362.2005.01555.x
发表时间：
2005-11-01
影响因子：
5.5
作者：
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通讯作者：
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DOI：
10.1016/j.bbrc.2006.03.015
发表时间：
2006-05-05
影响因子：
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作者：
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