Zhang Yanan, Zhang Chunlian, Li Haiou, Hou Jingdong
Department of Anesthesiology, Jining First People's Hospital, Jining, Shandong 272011, PR China.
Department of Surgery Operating Rooms, Jining First People's Hospital, Jining, Shandong 272011, PR China.
Biochem Biophys Res Commun. 2017 Oct 14;492(2):243-248. doi: 10.1016/j.bbrc.2017.08.058. Epub 2017 Aug 16.
Obstructive sleep apnea (OSA), characterized by chronic intermittent hypoxia (CIH), is associated with endothelial dysfunction. The prevalence of OSA is linked to an epidemic of obesity. CIH has recently been reported to cause endothelial dysfunction in diet-induced obese animals by exaggerating oxidative stress and inflammation, but the underlying mechanism remains unclear. PPAR-γ, a ligand-inducible transcription factor that exerts anti-oxidant and anti-inflammatory effects, is down-regulated in the peripheral tissues in diet-induce obesity. We tested the hypothesis that down-regulation of vascular PPAR-γ in diet-induced obesity enhances inflammation and oxidative stress in response to CIH, resulting in endothelial dysfunction. Male C57BL/6 mice were fed either a high-fat diet (HFD) or a low-fat diet (LFD) and simultaneously exposed to CIH or intermittent air for 6 weeks. An additional HFD group received a combination of CIH and PPAR-γ agonist pioglitazone for 6 weeks. Endothelial-dependent vasodilation was impaired only in HFD group exposed to CIH, compared with other groups, but was restored by concomitant pioglitazone treatment. Molecular studies revealed that vascular PPAR-γ expression and activity were reduced in HFD groups, compared with LFD groups, but were reversed by pioglitazone treatment. In addition, CIH elevated vascular expression of NADPH oxidase 4 and dihydroethidium fluorescence, and increased expression of proinflammatory cytokines TNF-α and IL-1β in both LFD and HFD groups, but these increases was significantly greater in HFD group, along with decreased vascular eNOS activity. Pioglitazone treatment of HFD group prevented CIH-induced changes in above molecular markers. The results suggest that HFD-induced obesity down-regulates vascular PPAR-γ, which results in exaggerated oxidative stress and inflammation in response to CIH, contributing to endothelial dysfunction. This finding may provide new insights into the mechanisms by which OSA induces endothelial dysfunction and other cardiovascular disease in patients with obesity.
阻塞性睡眠呼吸暂停（OSA）以慢性间歇性缺氧（CIH）为特征，与内皮功能障碍有关。OSA的患病率与肥胖流行相关。最近有报道称，CIH通过加剧氧化应激和炎症，导致饮食诱导的肥胖动物出现内皮功能障碍，但其潜在机制仍不清楚。PPAR-γ是一种配体诱导型转录因子，具有抗氧化和抗炎作用，在饮食诱导的肥胖外周组织中表达下调。我们检验了以下假设：饮食诱导的肥胖中血管PPAR-γ的下调会增强对CIH的炎症反应和氧化应激，从而导致内皮功能障碍。将雄性C57BL/6小鼠分为高脂饮食（HFD）组或低脂饮食（LFD）组，并同时暴露于CIH或间歇性空气环境中6周。另一个HFD组接受CIH与PPAR-γ激动剂吡格列酮联合处理6周。与其他组相比，仅暴露于CIH的HFD组内皮依赖性血管舒张功能受损，但吡格列酮联合处理可使其恢复。分子研究表明，与LFD组相比，HFD组血管PPAR-γ的表达和活性降低，但吡格列酮处理可使其逆转。此外，CIH使LFD组和HFD组血管NADPH氧化酶4的表达及二氢乙锭荧光增加，促炎细胞因子TNF-α和IL-1β的表达升高，但HFD组的这些增加更为显著，同时血管内皮型一氧化氮合酶（eNOS）活性降低。吡格列酮处理HFD组可预防CIH诱导的上述分子标志物变化。结果表明，HFD诱导的肥胖会下调血管PPAR-γ，导致对CIH反应时氧化应激和炎症加剧，进而导致内皮功能障碍。这一发现可能为OSA在肥胖患者中诱导内皮功能障碍及其他心血管疾病的机制提供新的见解。
