Telomere elongation protects heart and lung tissue cells from fatal damage in rats exposed to severe hypoxia

Springer Science and Business Media LLC - Tập 37 - Trang 1-6 - 2018
Yaping Wang1, Zhen Zhao1, Zhiyong Zhu1, Pingying Li1, Xiaolin Li1, Xiaohong Xue1, Jie Duo1, Yingcai Ma1
1Department of Digestion, Qinghai Provincial People’s Hospital, Xining, China

Tóm tắt

The effects of acute hypoxia at high altitude on the telomere length of the cells in the heart and lung tissues remain unclear. This study aimed to investigate the change in telomere length of rat heart and lung tissue cells in response to acute exposure to severe hypoxia and its role in hypoxia-induced damage to heart and lung tissues. Forty male Wistar rats (6-week old) were randomized into control group (n = 10) and hypoxia group (n = 30). Rats in control group were kept at an altitude of 1500 m, while rats in hypoxia group were exposed to simulated hypoxia with an altitude of 5000 m in a low-pressure oxygen chamber for 1, 3, and 7 days (n = 10). The left ventricular and right middle lobe tissues of each rat were collected for measurement of telomere length and reactive oxygen species (ROS) content, and the mRNA and protein levels of telomerase reverse transcriptase (TERT), hypoxia-inducible factor1α (HIF-1α), and hypoxia-inducible factor1α (HIF-2α). Increased exposure to hypoxia damaged rat heart and lung tissue cells and increased ROS production and telomere length. The mRNA and protein levels of TERT and HIF-1α were significantly higher in rats exposed to hypoxia and increased with prolonged exposure; mRNA and protein levels of HIF-2α increased only in rats exposed to hypoxia for 7 days. TERT was positively correlated with telomere length and the levels of HIF-1α but not HIF-2α. Acute exposure to severe hypoxia causes damage to heart and lung tissues due to the production of ROS but promotes telomere length and adaptive response by upregulating TERT and HIF-1α, which protect heart and lung tissue cells from fatal damage.

Tài liệu tham khảo

Davis C, Hackett P. Advances in the prevention and treatment of high altitude illness. Emerg Med Clin North Am. 2017;35(2):241–60. Riley CJ, Gavin M. Physiological changes to the cardiovascular system at high altitude and its effects on cardiovascular disease. High Alt Med Biol. 2017;18(2):102–13. Lu W, Zhang Y, Liu D, Songyang Z, Wan M. Telomeres structure, function, and regulation. Exp Cell Res. 2013;319(2):133–41. Blackburn EH. Switching and signaling at the telomere. Cell. 2001;106(6):661–73. Chan SR, Blackburn EH. Telomeres and telomerase. Philos Trans R Soc Lond Ser B Biol Sci. 2004;359(1441):109–21. Artandi SE. Telomeres, telomerase, and human disease. N Engl J Med. 2006;355(12):1195–7. Minamino T, Mitsialis SA, Kourembanas S. Hypoxia extends the life span of vascular smooth muscle cells through telomerase activation. Mol Cell Biol. 2001;21(10):3336–42. Kim KS, Kwak JW, Lim SJ, Park YK, Yang HS, Kim HJ. Oxidative stress-induced telomere length shortening of circulating leukocyte in patients with obstructive sleep apnea. Aging Dis. 2016;7(5):604–13. Wang YP, Zhao Z, Yang YZ, Zhao YX, Ge RL. Thymocytes maintain immune activity through telomere elongation in rats under hypoxic conditions. Exp Ther Med. 2015;10(5):1877–82. Wang YP, Zhu ZY, Tang Y, et al. Effects of acute hypoxia on telomere length of rat gastric mucosa tissue and underlying mechanism. Sheng Li Xue Bao. 2017;69(4):429–36. Wang Y, Yang Y, Ma L, Zhao Y, Bai Z, Ge R-L. Telomeres are elongated in rats exposed to moderate altitude. J Physiol Anthropol. 2014;33:19. Cataldi A, Zara S, Rapino M, Zingariello M, di Giacomo V, Antonucci A. p53 and telomerase control rat myocardial tissue response to hypoxia and ageing. Eur J Histochem. 2009;53(4):209–16. Roy S, Khanna S, Bickerstaff AA, Subramanian SV, Atalay M, Bierl M, Pendyala S, Levy D, Sharma N, Venojarvi M, Strauch A, Orosz CG, Sen CK. Oxygen sensing by primary cardiac fibroblasts: a key role of p21(Waf1/Cip1/Sdi1). Circ Res. 2003;92(3):264–71. Xu SL, Huang J, Zhu J, et al. Effects of hypoxia on promotor of TERT and cell cycle distribution in neonatal rat cardiac myocytes. Chin Med J. 2005;118(5):409–11. Mouraret N, Houssaïni A, Abid S, et al. Role for telomerase in pulmonary hypertension. Circulation. 2015;131(8):742–55. Holmquist-Mengelbier L, Fredlund E, Lofstedt T, Noguera R, Navarro S, Nilsson H, et al. Recruitment of HIF-1alpha and HIF-2alpha to common target genes is differentially regulated in neuroblastoma: HIF-2alpha promotes an aggressive phenotype. Cancer Cell. 2006;10:413–23. Nakamura TM, Morin GB, Chapman KB, Weinrich SL, Andrews WH, Lingner J, Harley CB, Cech TR. Telomerase catalytic subunit homologs from fission yeast and human. Science. 1997;277:955–9. Cheung AL, Deng W. Telomere dysfunction, genome instability and cancer. Front Biosci. 2008;13:2075–90. Fujiki T, Udono M, Kadooka K, Yamashita S, Miura T, Shirahata S, Katakura Y. Regulatory mechanisms of human and mouse telomerase reverse transcriptase gene transcription: distinct dependency on c-Myc. Cytotechnology. 2010;62:333–9. Wang Z, Xu J, Geng X, Zhang W. Analysis of DNA methylation status of the promoter of human telomerase reverse transcriptase in gastric carcinogenesis. Arch Med Res. 2010;41:1–6. Martin-Puig S, Temes E, Olmos G, Jones DR, Aragonés J, Landázuri MO. Role of iron(II)-2-oxoglutarate-dependent dioxygenases in the generation of hypoxia-induced phosphatidic acid through HIF-1/2 and von Hippel-Lindau-independent mechanisms. J Biol Chem. 2004;279(10):9504–11. Coussens M, Davy P, Brown L, Foster C, Andrews WH, Nagata M, Allsopp R. RNAi screen for telomerase reverse transcriptase transcriptional regulators identifies HIF1 alpha as critical for telomerase function in murine embryonic stem cells. Proc Natl Acad Sci U S A. 2010;107:13842–7. Yang K, Zheng D, Deng X, Bai L, Xu Y, Cong YS. Lysophosphatidic acid activates telomerase in ovarian cancer cells through hypoxia-inducible factor-1 alpha and the PI3K pathway. J Cell Biochem. 2008;105:1194–201. Koshikawa N, Hayashi J, Nakagawara A, Takenaga K. Reactive oxygen species-generating mitochondrial DNA mutation up-regulates hypoxia-inducible factor-1alpha gene transcription via phosphatidylinositol 3-kinase-Akt/protein kinase C/histone deacetylase pathway. J Biol Chem. 2009;284(48):33185–94.