Department of Cardiovascular Medicine, Mayo Clinic, MN, Rochester, USA.
Department of Surgery and Anatomy, Ribeirao Preto Medical School, Ribeirão Preto, SP, Brazil.
Sci Rep. 2020 Apr 22;10(1):6846. doi: 10.1038/s41598-020-63761-7.
Obstructive sleep apnea (OSA) is a common sleep disorder associated with obesity. Emerging evidence suggest that OSA increases the risk of cardiovascular morbidity and mortality partly via accelerating the process of cellular aging. Thus, we sought to examine the effects of intermittent hypoxia (IH), a hallmark of OSA, on senescence in human white preadipocytes. We demonstrate that chronic IH is associated with an increased generation of mitochondrial reactive oxygen species along with increased prevalence of cells with nuclear localization of γH2AX & p16. A higher prevalence of cells positive for senescence-associated β-galactosidase activity was also evident with chronic IH exposure. Intervention with aspirin, atorvastatin or renin-angiotensin system (RAS) inhibitors effectively attenuated IH-mediated senescence-like phenotype. Importantly, the validity of in vitro findings was confirmed by examination of the subcutaneous abdominal adipose tissue which showed that OSA patients had a significantly higher percentage of cells with nuclear localization of γH2AX & p16 than non-OSA individuals (20.1 ± 10.8% vs. 10.3 ± 2.7%, P < 0.001). Furthermore, the frequency of dual positive γH2AX & p16 nuclei in adipose tissue of OSA patients receiving statin, aspirin, and/or RAS inhibitors was comparable to non-OSA individuals. This study identifies chronic IH as a trigger of senescence-like phenotype in preadipocytes. Together, our data suggest that OSA may be considered as a senescence-related disorder.
阻塞性睡眠呼吸暂停（OSA）是一种与肥胖相关的常见睡眠障碍。新出现的证据表明，OSA 通过加速细胞衰老过程，增加心血管发病率和死亡率的风险。因此，我们试图研究间歇性低氧（IH），即 OSA 的一个标志，对人白色前体脂肪细胞衰老的影响。我们证明，慢性 IH 与线粒体活性氧的产生增加以及具有核定位的 γH2AX 和 p16 的细胞的患病率增加有关。慢性 IH 暴露也明显增加了衰老相关的β-半乳糖苷酶活性阳性细胞的数量。用阿司匹林、阿托伐他汀或肾素-血管紧张素系统（RAS）抑制剂进行干预可有效减轻 IH 介导的衰老样表型。重要的是，体外研究结果的有效性通过检查皮下腹部脂肪组织得到了证实，结果显示 OSA 患者具有核定位的 γH2AX 和 p16 的细胞比例明显高于非 OSA 个体（20.1±10.8%比 10.3±2.7%，P<0.001）。此外，在接受他汀类药物、阿司匹林和/或 RAS 抑制剂治疗的 OSA 患者的脂肪组织中，双重阳性 γH2AX 和 p16 核的频率与非 OSA 个体相当。这项研究确定了慢性 IH 是前体脂肪细胞衰老样表型的触发因素。总之，我们的数据表明，OSA 可被视为与衰老相关的疾病。
