Ding Wenxiao, Zhang Xiaofeng, Huang Hanpeng, Ding Ning, Zhang Shijiang, Hutchinson Sean Z, Zhang Xilong
Department of Respirology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China.
Department of Cardiothoracic Surgery, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China.
PLoS One. 2014 Apr 9;9(4):e94545. doi: 10.1371/journal.pone.0094545. eCollection 2014.
Obstructive sleep apnea syndrome (OSAS) is associated with many cardiovascular disorders such as heart failure, hypertension, atherosclerosis, and arrhythmia and so on. Of the many associated factors, chronic intermittent hypoxia (CIH) in particular is the primary player in OSAS. To assess the effects of CIH on cardiac function secondary to OSAS, we established a model to study the effects of CIH on Wistar rats. Specifically, we examined the possible underlying cellular mechanisms of hypoxic tissue damage and the possible protective role of adiponectin against hypoxic insults. In the first treatment group, rats were exposed to CIH conditions (nadir O2, 5-6%) for 8 hours/day, for 5 weeks. Subsequent CIH-induced cardiac dysfunction was measured by echocardiograph. Compared with the normal control (NC) group, rats in the CIH-exposed group experienced elevated levels of left ventricular end-systolic dimension and left ventricular end-systolic volume and depressed levels of left ventricular ejection fraction and left ventricular fractional shortening (p<0.05). However, when adiponectin (Ad) was added in CIH + Ad group, we saw a rescue in the elevations of the aforementioned left ventricular function (p<0.05). To assess critical cardiac injury, we detected myocardial apoptosis by Terminal deoxynucleotidyl transfer-mediated dUTP nick end-labeling (TUNEL) analysis. It was showed that the apoptosis percentage in CIH group (2.948%) was significantly higher than that in NC group (0.4167%) and CIH + Ad group (1.219%) (p<0.05). Protein expressions of cleaved caspase-3, cleaved caspase-9, and cleaved-caspase-12 validated our TUNEL results (p<0.05). Mechanistically, our results demonstrated that the proteins expressed with endoplasmic reticulum stress and the expression of reactive oxygen species (ROS) were significantly elevated under CIH conditions, whereas Ad supplementation partially decreased them. Overall, our results suggested that Ad augmentation could improve CIH-induced left ventricular dysfunction and associated myocardial apoptosis by inhibition of ROS-dependent ER stress.
阻塞性睡眠呼吸暂停综合征（OSAS）与许多心血管疾病相关，如心力衰竭、高血压、动脉粥样硬化和心律失常等。在众多相关因素中，慢性间歇性缺氧（CIH）尤其是OSAS的主要因素。为了评估CIH对OSAS继发心脏功能的影响，我们建立了一个模型来研究CIH对Wistar大鼠的影响。具体而言，我们研究了缺氧组织损伤可能的潜在细胞机制以及脂联素对缺氧损伤可能的保护作用。在第一个治疗组中，大鼠每天暴露于CIH条件（最低氧含量5 - 6%）下8小时，持续5周。随后通过超声心动图测量CIH诱导的心脏功能障碍。与正常对照组（NC）相比，CIH暴露组大鼠的左心室收缩末期内径和左心室收缩末期容积升高，左心室射血分数和左心室缩短分数降低（p<0.05）。然而，当在CIH + Ad组中加入脂联素（Ad）时，上述左心室功能的升高得到了缓解（p<0.05）。为了评估严重的心脏损伤，我们通过末端脱氧核苷酸转移酶介导的dUTP缺口末端标记（TUNEL）分析检测心肌细胞凋亡。结果显示，CIH组的凋亡百分比（2.948%）显著高于NC组（0.4167%）和CIH + Ad组（1.219%）（p<0.05）。裂解的半胱天冬酶-3、裂解的半胱天冬酶-9和裂解的半胱天冬酶-12的蛋白表达验证了我们的TUNEL结果（p<0.05）。从机制上讲，我们的结果表明，在内质网应激下表达的蛋白质和活性氧（ROS）的表达在CIH条件下显著升高，而补充Ad可部分降低它们。总体而言，我们的结果表明，增加Ad可以通过抑制ROS依赖性内质网应激来改善CIH诱导的左心室功能障碍和相关的心肌细胞凋亡。
