慢性间歇低氧上调心肌 lncRNA MALAT1 及相关分子的表达


目的通过观察长链非编码 RNA(lncRNA)中转移相关肺腺癌转录本 1(MALAT1)及其相关的炎症因子在不同低氧处理后心肌组织中的表达,探讨 MALAT1 在阻塞性睡眠呼吸暂停(OSA)导致心血管并发症中可能的作用机制。方法将成年 SD 大鼠随机分为持续低氧组(CH 组)、间歇低氧组(IH 组)、间歇低氧伴高二氧化碳组(IHH 组)并进行相应低氧处理,设置正常对照组(N 组),每组 8 只。上述处理分别进行 1 周、2 周、3 周后处死大鼠,提取大鼠心肌组织 RNA 样本,采用 qRT-PCR 法检测 MALAT1 基因的表达。结果干预 1 周时低氧处理的各组 MALAT1 基因表达较对照组有升高趋势,但差异无统计学意义。2 周和 3 周时,IHH 组大鼠心肌 MALAT1 基因的表达量较 IH 组、CH 组和 N 组均显著升高(均 P<0.01);IH 组、CH 组大鼠 MALAT1 基因的表达量较 N 组有升高趋势,但差异无统计学意义。低氧处理 3 周 IHH 组缺氧诱导因子-1α、Toll 样受体 4、白细胞介素-6 的 mRNA 表达量均较其他三组显著升高,与 MALAT1 的变化趋势一致。结论心肌 MALAT1 在低氧伴高二氧化碳处理后表达升高,与相关的重要缺氧及炎症因子上调趋势一致,提示 MALAT1 可能是 OSA 心肌免疫损伤的调控因子。

ObjectiveBy detecting the expression of the long non-coding RNA metastasis associated lung adenocarcinoma transcript 1 (MALAT1) in myocardial tissue under different hypoxia patterns, to explore the possible mechanism of obstructive sleep apnea (OSA)-induced cardiovascular diseases.MethodsSD rats were randomly and equally divided into 4 groups namely a normal (N) group, a continuous hypoxia (CH) group, an intermittent hypoxia (IH) group and an intermittent hypoxia with hypercapnia (IHH) group, and were treated for 1, 2, and 3 weeks. The expression of MALAT1 and associated immune factors of the myocardial tissue were examined by qRT-PCR.ResultsAn elevation without significance was observed in those three hypoxia groups in contrast with N group after 1 week’s treatment. However, in 2 and 3 weeks’ groups, the mRNA expression of MALAT1 was significantly higher in IHH group than the other three groups (all P<0.01), while there was no significant difference among IH, CH or N groups despite an increasing tendency in IH and CH groups against N group were observed. Additionally, the expressions of hypoxia inducible factor-1α (P<0.05), Toll-like receptor 4 (P<0.01) and interleukin-6 (P<0.05) mRNA were also increased significantly in IHH group compared with IH, CH and IHH groups in 3 weeks’ treatment respectively, which were coordinated with the change of MALAT1 mRNA.ConclusionsThe expression of MALAT1 in myocardial tissue is elevated by intermittent hypoxia with hypercapnia, and the tendency is similar with hypoxia-induced inflammation factors. These findings indicate that MALAT1 is probably a regulatory factor of OSA induced myocardial immune injury.

关键词: 阻塞性睡眠呼吸暂停; 长链非编码 RNA; 间歇低氧; 高二氧化碳血症; 炎症

Key words: Obstructive sleep apnea; Long non-coding RNA; Intermitted hypoxia; Hypercapnia; Inflammation

引用本文: 陈凤惟, 张成, 董慧, 王奇敏, 马靖, 王广发. 慢性间歇低氧上调心肌 lncRNA MALAT1 及相关分子的表达. 中国呼吸与危重监护杂志, 2018, 17(4): 377-382. doi: 10.7507/1671-6205.201710025 复制

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1. Drager LF, Togeiro SM, Polotsky VY, et al. Obstructive sleep apnea: a cardiometabolic risk in obesity and the metabolic syndrome. J Am Coll Cardiol, 2013, 62(7): 569-576.
2. Crifo B, Taylor CT. Crosstalk between toll-like receptors and hypoxia-dependent pathways in health and disease. J Investig Med, 2016, 64(2): 369-375.
3. Unnikrishnan D, Jun J, Polotsky V. Inflammation in sleep apnea: an update. Rev Endocr Metab Disord, 2015, 16(1): 25-34.
4. Chen YG, Satpathy AT, Chang HY. Gene regulation in the immune system by long noncoding RNAs. Nat Immunol, 2017, 18(9): 962-972.
5. Mazidi M, Penson P, Gluba-Brzozka A, et al. Relationship between long noncoding RNAs and physiological risk factors of cardiovascular disease. J Clin Lipidol, 2017, 11(3): 617-623.
6. Boon RA, Jae N, Holdt L, et al. Long Noncoding RNAs: From Clinical Genetics to Therapeutic Targets?. J Am Coll Cardiol, 2016, 67(10): 1214-1226.
7. Tripathi V, Ellis JD, Shen Z, et al. The nuclear-retained noncoding RNA MALAT1 regulates alternative splicing by modulating SR splicing factor phosphorylation. Mol Cell, 2010, 39(6): 925-938.
8. Tripathi V, Shen Z, Chakraborty A, et al. Long noncoding RNA MALAT1 controls cell cycle progression by regulating the expression of oncogenic transcription factor B-MYB. PLoS Genet, 2013, 9(3): e1003368.
9. Michalik KM, You X, Manavski Y, et al. Long noncoding RNA MALAT1 regulates endothelial cell function and vessel growth. Circ Res, 2014, 114(9): 1389-1397.
10. Luo F, Liu X, Ling M, et al. The lncRNA MALAT1, acting through HIF-1alpha stabilization, enhances arsenite-induced glycolysis in human hepatic L-02 cells. Biochim Biophys Acta, 2016, 1862(9): 1685-1695.
11. Salle-Lefort S, Miard S, Nolin MA, et al. Hypoxia upregulates Malat1 expression through a CaMKK/AMPK/HIF-1alpha axis. Int J Oncol, 2016, 49(4): 1731-1736.
12. Liu JY, Yao J, Li XM, et al. Pathogenic role of lncRNA-MALAT1 in endothelial cell dysfunction in diabetes mellitus. Cell Death Dis, 2014, 5(10): e1506.
13. Lelli A, Nolan KA, Santambrogio S, et al. Induction of long noncoding RNA MALAT1 in hypoxic mice. Hypoxia(Auckl), 2015, 3(default): 45-52.
14. Vausort M, Wagner DR, Devaux Y. Long noncoding RNAs in patients with acute myocardial infarction. Circ Res, 2014, 115(7): 668-677.
15. Puthanveetil P, Chen S, Feng B, et al. Long non-coding RNA MALAT1 regulates hyperglycaemia induced inflammatory process in the endothelial cells. J Cell Mol Med, 2015, 19(6): 1418-1425.
16. Zhao G, Su Z, Song D, et al. The long noncoding RNA MALAT1 regulates the lipopolysaccharide-induced inflammatory response through its interaction with NF-kappaB. FEBS Lett, 2016, 590(17): 2884-2895.
17. Zhuang YT, Xu DY, Wang GY, et al. IL-6 induced lncRNA MALAT1 enhances TNF-alpha expression in LPS-induced septic cardiomyocytes via activation of SAA3. Eur Rev Med Pharmacol Sci, 2017, 21(2): 302-309.
18. Zhang X, Tang X, Liu K, et al. Long Noncoding RNA Malat1 Regulates Cerebrovascular Pathologies in Ischemic Stroke. J Neurosci, 2017, 37(7): 1797-1806.
19. Curley G, Laffey JG, Kavanagh BP. Bench-to-bedside review: carbon dioxide. Crit Care, 2010, 14(2): 220.
20. Yamaguchi T, Yamazaki T, Nakamura Y, et al. Percutaneous carbon dioxide mist treatment has protective effects in experimental myocardial infarction. J Pharmacol Sci, 2015, 127(4): 474-480.
21. Laffey JG, Honan D, Hopkins N, et al. Hypercapnic acidosis attenuates endotoxin-induced acute lung injury. Am J Respir Crit Care Med, 2004, 169(1): 46-56.
22. Brzecka A. Role of hypercapnia in brain oxygenation in sleep-disordered breathing. Acta Neurobiol Exp(Wars), 2007, 67(2): 197-206.
23. Amato MB, Barbas CS, Medeiros DM, et al. Effect of a protective-ventilation strategy on mortality in the acute respiratory distress syndrome. N Engl J Med, 1998, 338(6): 347-354.
24. Dergacheva O, Dyavanapalli J, Pinol RA, et al. Chronic intermittent hypoxia and hypercapnia inhibit the hypothalamic paraventricular nucleus neurotransmission to parasympathetic cardiac neurons in the brain stem. Hypertension, 2014, 64(3): 597-603.
25. Cummins EP, Oliver KM, Lenihan CR, et al. NF-kappaB links CO2 sensing to innate immunity and inflammation in mammalian cells. J Immunol, 2010, 185(7): 4439-4445.
26. Abolhassani M, Guais A, Chaumet-Riffaud P, et al. Carbon dioxide inhalation causes pulmonary inflammation. Am J Physiol Lung Cell Mol Physiol, 2009, 296(4): L657-665.
27. Nichol AD, O'Cronin DF, Howell K, et al. Infection-induced lung injury is worsened after renal buffering of hypercapnic acidosis. Crit Care Med, 2009, 37(11): 2953-2961.
28. Hanly EJ, Mendoza-Sagaon M, Murata K, et al. CO2 pneumoperitoneum modifies the inflammatory response to sepsis. Ann Surg, 2003, 237(3): 343-350.