Role of ROS/Kv/HIF Axis in the Development of Hypoxia-Induced Pulmonary Hypertension

Wu Wen; Li Yan; Xu Dunquan

doi:10.24920/J1001-9294.2017.037

Your Location：

Home >

Browse articles >

Role of ROS/Kv/HIF Axis in the Development of Hypoxia-Induced Pulmonary Hypertension

Chinese Medical Sciences Journal Vol. 32, Issue 4, Pages: 253-259(2017)

REVIEW | Updated：2024-04-10

- Role of ROS/Kv/HIF Axis in the Development of Hypoxia-Induced Pulmonary Hypertension
- Affiliations：
  
  1. 1Department of Ultrasound, General Hospital of the Army, Beijing 100007, China
  2. 2.Medical Examination Center, General Hospital of the Army, Beijing 100007, China
  3. 3Clinical Laboratory, the Xigaze Branch of Xinqiao Hospital, the Army Medical University, Xigaze, Tibet 857000, China
- Author bio：
  
  Corresponding author Tel: 86-17710560131, E-mail:149011273@qq.com
- Funds：
- DOI：10.24920/J1001-9294.2017.037
  CLC：
- Received：24 October 2016，
  
  Published Online：30 December 2017，
  
  Published：2017-12
- Accepted：
Scan QR Code
Wu Wen, Li Yan, Xu Dunquan. Role of ROS/Kv/HIF Axis in the Development of Hypoxia-Induced Pulmonary Hypertension[J]. Chinese medical sciences journal, 2017, 32(4): 253-259.
DOI：

Wu Wen, Li Yan, Xu Dunquan. Role of ROS/Kv/HIF Axis in the Development of Hypoxia-Induced Pulmonary Hypertension[J]. Chinese medical sciences journal, 2017, 32(4): 253-259. DOI： 10.24920/J1001-9294.2017.037.

摘要

低氧性肺动脉高压是常见于慢性阻塞性病

睡眠呼吸障碍性疾病

或久居高海拔的居民所患的一种严重并发症。目前关于低氧性肺动脉高压确切的发病机制仍不完全明了。活性氧簇

低氧诱导因子和钾离子通道被认为在低氧性肺动脉高压的发生发展中起重要作用。在此我们认为“活性氧簇/钾离子通道/低氧诱导因子”轴在低氧性肺动脉高压的发生发展中可能起到触发作用。活性氧簇首先产生于低氧环境

其后影响低氧诱导因子和钾离子通道的表达

继而触发下游多条途径参与肺动脉血管收缩和血管重构的各种基因和信号因子的表达。因此

研究“活性氧簇/钾离子通道/低氧诱导因子”轴在低氧性肺动脉高压发生发展中的作用将会为揭示低氧性肺动脉高压的发生机制提供理论依据

并有助于为肺动脉高压提供潜在的治疗靶点。

Abstract

Hypoxic pulmonary hypertension (HPH) is a common complication in patients with chronic obstructive pulmonary disease (COPD)

sleep-disordered breathing

or dwellers in high altitude. The exact mechanisms underlying the development of HPH still remain unclear. Reactive oxygen species (ROS)

hypoxia inducible factors (HIF)

and potassium channels (K

) are believed as the main factors during the development of HPH. We propose that the “ROS/Kv/HIF axis” may play an important initiating role in the development of HPH. Being formed under a hypoxic condition

ROS affects the expression and function of HIFs or K

and consequently triggers multiple downstream signaling pathways and genes expression that participate in promoting pulmonary vasoconstriction and arterial remodeling. Thus

further study determining the initiating role of “ROS/Kv/HIF axis” in the development of HPH could provide theoretic evidences to better understand the underlying mechanisms of HPH

and help identify new potential targets in the treatment of HPH.

关键词

Keywords

references

Shah SJ. Pulmonary hypertension. JAMA 2012 ; 308 : 1366 - 74 . doi: 10.1001/jama.2012.12347 https://doi.org/10.1001/jama.2012.12347 .

Galiè N , Hoeper MM , Humbert M , Torbicki A , Vachiery JL , Barbera JA , et al. Guidelines for the diagnosis and treatment of pulmonary hypertension: the Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT). Eur Heart J 2009 ; 30 : 2493 - 537 . doi: 10.1093/eurheartj/ehp297 https://doi.org/10.1093/eurheartj/ehp297 .

Sylvester JT , Shimoda LA , Aaronson PI , Ward JP. Hypoxic pulmonary vasoconstriction. Physiol Rev 2012 ; 92 : 367 - 520 . doi: 10.1152/physrev.00041.2010 https://doi.org/10.1152/physrev.00041.2010 .

Stenmark KR , Fagan KA , Frid MG. Hypoxia-induced pulmonary vascular remodeling: cellular and molecular mech- anisms. Circ Res 2006 ; 99 : 675 - 91 . doi: 10.1161/01.RES. 0000243584.45145.3f https://doi.org/10.1161/01.RES.0000243584.45145.3f .

Stenmark KR , Davie N , Frid M , Gerasimovskaya E , Das M. Role of the adventitia in pulmonary vascular remodeling. Physiology (Bethesda) 2006 ; 21 : 134 - 45 . doi: 10.1152/physiol.00053.2005 https://doi.org/10.1152/physiol.00053.2005 .

Sommer N , Dietrich A , Schermuly RT , Ghofrani HA , Gudermann T , Schulz R , et al. Regulation of hypoxic pulmonary vasoconstriction: basic mechanisms. Eur Respir J 2008 ; 32 : 1639 - 51 . doi: 10.1183/09031936.00013908 https://doi.org/10.1183/09031936.00013908 .

Liu JQ , Zelko IN , Erbynn EM , Sham JS , Folz RJ. Hypoxic pulmonary hypertension: role of superoxide and NADPH oxidase (gp91phox). Am J Physiol Lung Cell Mol Physiol 2006 ; 290 : L2 - 10 . doi: 10.1152/ajplung.00135.2005 https://doi.org/10.1152/ajplung.00135.2005 .

Jankov RP , Kantores C , Pan J , Belik J. Contribution of xanthine oxidase-derived superoxide to chronic hypoxic pulmonary hypertension in neonatal rats. Am J Physiol Lung Cell Mol Physiol 2008 ; 294 : L233 - 45 . doi: 10.1152/ajplung.00166.2007 https://doi.org/10.1152/ajplung.00166.2007 .

Mittal M , Gu XQ , Pak O , Pamenter ME , Haag D , Fuchs DB , et al. Hypoxia induces Kv channel current inhibition by increased NADPH oxidase-derived reactive oxygen species. Free Radic Biol Med 2012 ; 52 : 1033 - 42 . doi: 10.1016/j.freeradbiomed.2011.12.004 https://doi.org/10.1016/j.freeradbiomed.2011.12.004 .

Xu S , Touyz RM. Reactive oxygen species and vascular remodelling in hypertension: still alive. Can J Cardiol 2006 ; 22 : 947 - 51 . doi: 10.1016/s0828-282x(06)70314-2 https://doi.org/10.1016/s0828-282x(06)70314-2 .

Wong CM , Bansal G , Pavlickova L , Marcocci L , Suzuki YJ. Reactive oxygen species and antioxidants in pulmonary hypertension. Antioxid Redox Signal 2013 ; 1 : 1789 - 96 . doi: 10.1089/ars.2012.4568 https://doi.org/10.1089/ars.2012.4568 .

Voelkel NF , Bogaard HJ , Al Husseini A , Farkas L , Gomez-Arroyo J , Natarajan R. Antioxidants for the treatment of patients with severe angioproliferative pulmonary hypertension? Antioxid Redox Signal 2013 ; 18 : 1810 - 7 . doi: 10.1089/ars.2012.4828 https://doi.org/10.1089/ars.2012.4828 .

Waypa GB , Guzy R , Mungai PT , Mack MM , Marks JD , Roe MW , et al. Increases in mitochondrial reactive oxygen species trigger hypoxia-induced calcium responses in pulmonary artery smooth muscle cells. Circ Res 2006 ; 99 : 970 - 8 . doi: 10.1161/01.RES.0000247068.75808.3f https://doi.org/10.1161/01.RES.0000247068.75808.3f .

Radak Z , Zhao Z , Koltai E , Ohno H , Atalay M. Oxygen consumption and usage during physical exercise: the balance between oxidative stress and ROS-dependent adaptive signaling. Antioxid Redox Signal 2013 ; 18 : 1208 - 46 . doi: 10.1089/ars.2011.4498 https://doi.org/10.1089/ars.2011.4498 .

Freund-Michel V , Guibert C , Dubois M , Courtois A , Marthan R , Savineau JP , et al. Reactive oxygen species as therapeutic targets in pulmonary hypertension. Ther Adv Respir Dis 2013 ; 7 : 175 - 200 . doi: 10.1177/1753465812 472940 https://doi.org/10.1177/1753465812 472940 .

Semenza GL. Hypoxia-inducible factor 1: control of oxygen homeostasis in health and disease. Pediatr Res 2001 ; 49 : 614 - 7 . doi: 10.1203/00006450-200105000-00002 https://doi.org/10.1203/00006450-200105000-00002 .

Semenza GL. Oxygen sensing, homeostasis, and disease. N Engl J Med 2011 ; 365 : 537 - 47 . doi: 10.1056/NEJMra 1011165 https://doi.org/10.1056/NEJMra 1011165 .

Hagen T. Oxygen versus Reactive Oxygen in the Regulation of HIF-1alpha: The Balance Tips. Biochem Res Int 2012 ; 436981 . doi: 10.1155/2012/436981 https://doi.org/10.1155/2012/436981 .

Masson N , Singleton RS , Sekirnik R , Trudgian DC , Ambrose LJ , Miranda MX , et al. The FIH hydroxylase is a cellular peroxide sensor that modulates HIF transcriptional activity. EMBO Rep 2012 ; 13 : 251 - 7 . doi: 10.1038/ embor.2012.9 https://doi.org/10.1038/ embor.2012.9 .

Chua YL , Dufour E , Dassa EP , Rustin P , Jacobs HT , Taylor CT , et al. Stabilization of hypoxia-inducible factor-1alpha protein in hypoxia occurs independently of mitochondrial reactive oxygen species production. J Biol Chem 2010 ; 285 : 31277 - 84 . doi: 10.1074/jbc.M110.158485 https://doi.org/10.1074/jbc.M110.158485 .

Brown ST , Nurse CA. Induction of HIF-2alpha is dependent on mitochondrial O 2 consumption in an O 2 -sensitive adrenomedullary chromaffin cell line. Am J Physiol Cell Physiol 2008 ; 294 : C1305 - 12 . doi: 10.1152/ajpcell.00007. 2008 https://doi.org/10.1152/ajpcell.00007. 2008 .

Calvani M , Comito G , Giannoni E , Chiarugi P. Time-dependent stabilization of hypoxia inducible factor-1alpha by different intracellular sources of reactive oxygen species. Plos One 2012 ; 7 : e38388 . doi: 10.1371/journal.pone. 0038388 https://doi.org/10.1371/journal.pone. 0038388 .

Prabhakar NR , Semenza GL. Adaptive and maladaptive cardiorespiratory responses to continuous and intermittent hypoxia mediated by hypoxia-inducible factors 1 and 2. Physiol Rev 2012 ; 92 : 967 - 1003 . doi: 10.1152/physrev. 00030.2011 https://doi.org/10.1152/physrev. 00030.2011 .

Semenza GL , Prabhakar NR. The role of hypoxia-inducible factors in oxygen sensing by the carotid body. Adv Exp Med Biol 2012 ; 758 : 1 - 5 . doi: 10.1007/978-94-007-4584-1_1 https://doi.org/10.1007/978-94-007-4584-1_1 .

Archer SL , Wu XC , Thébaud B , Nsair A , Bonnet S , Tyrrell B , et al. Preferential expression and function of voltage-gated, O 2 -sensitive K+ channels in resistance pulmonary arteries explains regional heterogeneity in hypoxic pulmonary vasoconstriction: ionic diversity in smooth muscle cells. Circ Res 2004 ; 95 : 308 - 18 . doi: 10.1161/01.RES.0000137173.42723.fb https://doi.org/10.1161/01.RES.0000137173.42723.fb .

Ouyang JS , Li YP , Li CY , Cai C , Chen CS , Chen SX , et al. Mitochondrial ROS-K+ channel signaling pathway regulated secretion of human pulmonary artery endothelial cells. Free Radic Res 2012 ; 46 : 1437 - 45 . doi: 10.3109/ 10715762.2012.724532 https://doi.org/10.3109/10715762.2012.724532 .

Yasui S , Mawatari K , Morizumi R , Furukawa H , Shimohata T , Harada N , et al. Hydrogen peroxide inhibits insulin-induced ATP-sensitive potassium channel activation independent of insulin signaling pathway in cultured vascular smooth muscle cells. J Med Invest 2012 ; 59 : 36 - 44 . doi: 10.2152/jmi.59.36 https://doi.org/10.2152/jmi.59.36 .

Wang YX , Zheng YM. Role of ROS signaling in differential hypoxic Ca 2 + and contractile responses in pulmonary and systemic vascular smooth muscle cells. Respir Physiol Neurobiol 2010 ; 174 : 192 - 200 . doi: 10.1016/j.resp.2010.08.008 https://doi.org/10.1016/j.resp.2010.08.008 .

29.Rathore R , Zheng YM , Niu CF , Furukawa H , Shimohata T , Harada N , et al . Hypoxia activates NADPH oxidase to increase [ROS]i and [Ca 2 +]i through the mitochondrial ROS-PKCepsilon signaling axis in pulmonary artery smooth muscle cells. Free Radic Biol Med 2008 ; 45 : 1223 - 31 . doi: 10.1016/j.freeradbiomed.2008.06.012 https://doi.org/10.1016/j.freeradbiomed.2008.06.012 .

. Lachmanová V , Hnilicková O , Povýsilová V , Hampl V , Herget J. N-acetylcysteine inhibits hypoxic pulmonary hypertension most effectively in the initial phase of chronic hypoxia. Life Sci 2005 ; 77 : 175 - 82 . doi: 10.1016/j.lfs.2004.11.027 https://doi.org/10.1016/j.lfs.2004.11.027 .

Liu Y , Bubolz AH , Mendoza S , Zhang DX , Gutterman DD. H2O2 is the transferrable factor mediating flow-induced dilation in human coronary arterioles. Circ Res 2011 ; 108 : 566 - 73 . doi: 10.1161/CIRCRESAHA.110.237636 https://doi.org/10.1161/CIRCRESAHA.110.237636 .

Zhang DX , Borbouse L , Gebremedhin D , Mendoza SA , Zinkevich NS , Li R , et al. H2O2-induced dilation in human coronary arterioles: role of protein kinase G dimerization and large-conductance Ca 2 +-activated K+ channel activation. Circ Res 2012 ; 110 : 471 - 80 . doi: 10.1161/CIRCRE-SAHA.111.258871 https://doi.org/10.1161/CIRCRE-SAHA.111.258871 .

Hu CJ , Iyer S , Sataur A , Covello KL , Chodosh LA , Simon MC. Differential regulation of the transcriptional activities of hypoxia-inducible factor 1 alpha (HIF-1alpha) and HIF-2alpha in stem cells. Mol Cell Biol 2006 ; 26 : 3514 - 26 . doi: 10.1128/MCB.26.9.3514-3526.2006 https://doi.org/10.1128/MCB.26.9.3514-3526.2006 .

Rankin EB , Giaccia AJ. Hypoxic control of metastasis. Science 2016 ; 352 ( 6282 ): 175 - 80 . doi: 10.1126/science.aaf4405 https://doi.org/10.1126/science.aaf4405 .

Smith KA , Yuan JX. Hypoxia-inducible factor-1alpha in pulmonary arterial smooth muscle cells and hypoxia- induced pulmonary hypertension. Am J Respir Crit Care Med 2014 ; 189 : 245 - 6 . doi: 10.1164/rccm.201312-2148ED https://doi.org/10.1164/rccm.201312-2148ED .

Zhao J , Du F , Shen G , Zheng F , Xu B. The role of hypoxia-inducible factor-2 in digestive system cancers. Cell Death Dis 2015 ; 6 : e1600 . doi: 10.1038/cddis.2014.565 https://doi.org/10.1038/cddis.2014.565 .

Yang SL , Liu LP , Niu L , Sun YF , Yang XR , Fan J , et al. Downregulation and pro-apoptotic effect of hypoxia- inducible factor 2 alpha in hepatocellular carcinoma. Oncotarget 2016 ; 7 : 34571 - 81 . doi: 10.18632/oncotarget. 8952 https://doi.org/10.18632/oncotarget.8952 .

Huang LE , Gu J , Schau M , Bunn HF. Regulation of hypoxia-inducible factor 1alpha is mediated by an O2-dependent degradation domain via the ubiquitin-proteasome pathway. Proc Natl Acad Sci USA 1998 ; 95 : 7987 - 92 . doi: 10.1073/pnas.95.14.7987 https://doi.org/10.1073/pnas.95.14.7987 .

Semenza GL. HIF-1: mediator of physiological and pathophysiological responses to hypoxia. J Appl Physiol 2000 ; 88 : 1474 - 80 . doi: 10.1152/jappl.2000.88.4.1474 https://doi.org/10.1152/jappl.2000.88.4.1474 .

Prabhakar NR , Kumar GK , Peng YJ. Sympatho-adrenal activation by chronic intermittent hypoxia. J Appl Physiol 2012 ; 113 : 1304 - 10 . doi: 10.1152/japplphysiol.00444.2012 https://doi.org/10.1152/japplphysiol.00444.2012 .

Kato M , Staub NC. Response of small pulmonary arteries to unilobar hypoxia and hypercapnia. Circ Res 1966 ; 19 : 426 - 40 . doi: 10.1161/01.res.19.2.426 https://doi.org/10.1161/01.res.19.2.426 .

Madden JA , Vadula MS , Kurup VP. Effects of hypoxia and other vasoactive agents on pulmonary and cerebral artery smooth muscle cells. Am J Physiol 1992 ; 263 : L384 - 93 . doi: 10.1152/ajplung.1992.263.3.L384 https://doi.org/10.1152/ajplung.1992.263.3.L384 .

Vadula MS , Kleinman JG , Madden JA. Effect of hypoxia and norepinephrine on cytoplasmic free Ca 2 + in pulmonary and cerebral arterial myocytes. Am J Physiol 1993 ; 265 : L591 - 7 . doi: 10.1152/ajplung.1993.265.6.L591 https://doi.org/10.1152/ajplung.1993.265.6.L591 .

Archer S , Michelakis E. The mechanism(s) of hypoxic pulmonary vasoconstriction: potassium channels, redox O(2) sensors, and controversies. News Physiol Sci 2002 ; 17 : 131 - 7 . doi: 10.1152/nips.01388.2002 https://doi.org/10.1152/nips.01388.2002 .

Hall SM , Hislop AA , Pierce CM , Haworth SG. Prenatal origins of human intrapulmonary arteries: formation and smooth muscle maturation. Am J Respir Cell Mol Biol 2000 ; 23 : 194 - 203 . doi: 10.1165/ajrcmb.23.2.3975 https://doi.org/10.1165/ajrcmb.23.2.3975 .

Mironova GD , Shigaeva MI , Gritsenko EN , Murzaeva SV , Gorbacheva OS , Germanova EL , et al. Functioning of the mitochondrial ATP-dependent potassium channel in rats varying in their resistance to hypoxia. Involvement of the channel in the process of animal's adaptation to hypoxia. J Bioenerg Biomembr 2010 ; 42 : 473 - 81 . doi: 10.1007/s10863-010-9316-5 https://doi.org/10.1007/s10863-010-9316-5 .

Brown ST , Buttigieg J , Nurse CA. Divergent roles of reactive oxygen species in the responses of perinatal adrenal chromaffin cells to hypoxic challenges. Respir Physiol Neurobiol 2010 ; 174 : 252 - 8 . doi: 10.1016/j.resp. 2010.08.020 https://doi.org/10.1016/j.resp.2010.08.020 .

Dong Q , Zhao N , Xia CK , Du LL , Fu XX , Du YM. Hypoxia induces voltage-gated K+ (Kv) channel expression in pulmonary arterial smooth muscle cells through hypoxia-inducible factor-1 (HIF-1). Bosn J Basic Med Sci 2012 ; 12 : 158 - 63 . doi: 10.17305/bjbms.2012.2463 https://doi.org/10.17305/bjbms.2012.2463 .

Shin DH , Lin H , Zheng H , Kim KS , Kim JY , Chun YS , et al. HIF-1alpha-mediated upregulation of TASK-2 K+ channels augments Ca 2 + signaling in mouse B cells under hypoxia. J Immunol 2014 ; 193 : 4924 - 33 . doi: 10.4049/ jimmunol.1301829 https://doi.org/10.4049/jimmunol.1301829 .

Views

1856

Downloads

CSCD

Alert me when the article has been cited

Submit

Publicity Resources

No data

Related Author

No data

Related Institution

No data

⁰