Clinical and Experimental Pediatrics

The Korean Pediatric Society (대한소아청소년과학회)
권호 표지
DOI QR코드

DOI QR Code

Change of voltage-gated potassium channel 1.7 expressions in monocrotaline-induced pulmonary arterial hypertension rat model

  • Lee, Hyeryon (Department of Pediatrics, Ewha Womans University School of Medicine) ;
  • Kim, Kwan Chang (Department of Thoracic and Cardiovascular Surgery, Ewha Womans University School of Medicine) ;
  • Hong, Young Mi (Department of Pediatrics, Ewha Womans University School of Medicine)
  • Received : 2018.03.16
  • Accepted : 2018.06.01
  • Published : 2018.09.15
Download PDF
⟨ Previous Next ⟩

Abstract

Purpose: Abnormal potassium channels expression affects vessel function, including vascular tone and proliferation rate. Diverse potassium channels, including voltage-gated potassium (Kv) channels, are involved in pathological changes of pulmonary arterial hypertension (PAH). Since the role of the Kv1.7 channel in PAH has not been previously studied, we investigated whether Kv1.7 channel expression changes in the lung tissue of a monocrotaline (MCT)-induced PAH rat model and whether this change is influenced by the endothelin (ET)-1 and reactive oxygen species (ROS) pathways. Methods: Rats were separated into 2 groups: the control (C) group and the MCT (M) group (60 mg/kg MCT). A hemodynamic study was performed by catheterization into the external jugular vein to estimate the right ventricular pressure (RVP), and pathological changes in the lung tissue were investigated. Changes in protein and mRNA levels were confirmed by western blot and polymerase chain reaction analysis, respectively. Results: MCT caused increased RVP, medial wall thickening of the pulmonary arterioles, and increased expression level of ET-1, ET receptor A, and NADPH oxidase (NOX) 4 proteins. Decreased Kv1.7 channel expression was detected in the lung tissue. Inward-rectifier channel 6.1 expression in the lung tissue also increased. We confirmed that ET-1 increased NOX4 level and decreased glutathione peroxidase-1 level in pulmonary artery smooth muscle cells (PASMCs). ET-1 increased ROS level in PASMCs. Conclusion: Decreased Kv1.7 channel expression might be caused by the ET-1 and ROS pathways and contributes to MCT-induced PAH.

Keywords

References

  1. Humbert M, Morrell NW, Archer SL, Stenmark KR, MacLean MR, Lang IM, et al. Cellular and molecular pathobiology of pulmonary arterial hypertension. J Am Coll Cardiol 2004;43:13-24.
  2. Ward JPT. Physiological redox signalling and regulation of ion channels: implications for pulmonary hypertension. Exp Physiol 2017;102:1078-82. https://doi.org/10.1113/EP086040
  3. Bonnet S, Archer SL. Potassium channel diversity in the pulmonary arteries and pulmonary veins: implications for regulation of the pulmonary vasculature in health and during pulmonary hypertension. Pharmacol Ther 2007;115:56-69. https://doi.org/10.1016/j.pharmthera.2007.03.014
  4. Burg ED, Remillard CV, Yuan JX. Potassium channels in the regulation of pulmonary artery smooth muscle cell proliferation and apoptosis:pharmacotherapeutic implications. Br J Pharmacol 2008;153:S99-111.
  5. Whitman EM, Pisarcik S, Luke T, Fallon M, Wang J, Sylvester JT, et al. Endothelin-1 mediates hypoxia-induced inhibition of voltagegated K+ channel expression in pulmonary arterial myocytes. Am J Physiol Lung Cell Mol Physiol 2008;294:309-18. https://doi.org/10.1152/ajplung.00091.2007
  6. Archer SL, Souil E, Dinh-Xuan AT, Schremmer B, Mercier JC, El Yaagoubi A, et al. Molecular identification of the role of voltagegated K+ channels, Kv1.5 and Kv2.1, in hypoxic pulmonary vasoconstriction and control of resting membrane potential in rat pulmonary artery myocytes. J Clin Invest 1998;101:2319-30. https://doi.org/10.1172/JCI333
  7. Yuan XJ. Voltage-gated K+ currents regulate resting membrane potential and [Ca2+] in pulmonary arterial myocytes. Circ Res 1995;77:370-8. https://doi.org/10.1161/01.RES.77.2.370
  8. Wedgwood S, Dettman RW, Black SM. ET-1 stimulates pulmonary arterial smooth muscle cell proliferation via induction of reactive oxygen species. Am J Physiol Lung Cell Mol Physiol 2001;281:1058-67. https://doi.org/10.1152/ajplung.2001.281.5.L1058
  9. Miyauchi T, Yorikane R, Sakai S, Sakurai T, Okada M, Nishikibe M, et al. Contribution of endogenous endothelin-1 to the progression of cardiopulmonary alterations in rats with monocrotaline-induced pulmonary hypertension. Circ Res 1993;73:887-97. https://doi.org/10.1161/01.RES.73.5.887
  10. Cogolludo A, Frazziano G, Cobeno L, Moreno L, Lodi F, Villamor E, et al. Role of reactive oxygen species in Kv channel inhibition and vasoconstriction induced by TP receptor activation in rat pulmonary arteries. Ann N Y Acad Sci 2006;1091:41-51. https://doi.org/10.1196/annals.1378.053
  11. Fulton DJR, Li X, Bordan Z, Haigh S, Bentley A, Chen F, et al. Reactive oxygen and nitrogen species in the development of pulmonary hypertension. Antioxidants (Basel) 2017;6:54-76. https://doi.org/10.3390/antiox6030054
  12. Nelson MT, Quayle JM. Physiological roles and properties of potassium channels in arterial smooth muscle. Am J Physiol 1995;268:799-822. https://doi.org/10.1152/ajpcell.1995.268.4.C799
  13. Shibukawa Y, Chilton EL, Maccannell KA, Clark RB, Giles WR. K+ currents activated by depolarization in cardiac fibroblasts. Biophys J 2005;88:3924-35. https://doi.org/10.1529/biophysj.104.054429
  14. Wedgwood S, McMullan DM, Bekker JM, Fineman JR, Black SM. Role for endothelin-1-induced superoxide and peroxynitrite production in rebound pulmonary hypertension associated with inhaled nitric oxide therapy. Circ Res 2001;89:357-64. https://doi.org/10.1161/hh1601.094983
  15. Lee H, Kim KC, Cho MS, Suh SH, Hong YM. Modafinil improves monocrotaline-induced pulmonary hypertension rat model. Pediatr Res 2016;80:119-27. https://doi.org/10.1038/pr.2016.38
  16. Archer SL, Gomberg-Maitland M, Maitland ML, Rich S, Garcia JG, Weir EK. Mitochondrial metabolism, redox signaling, and fusion: a mitochondria-ROS-HIF-1 alpha-Kv1.5 O2-sensing pathway at the intersection of pulmonary hypertension and cancer. Am J Physiol Heart Circ Physiol 2008;294:570-8. https://doi.org/10.1152/ajpheart.01324.2007
  17. Shimoda LA, Sylvester JT, Booth GM, Shimoda TH, Meeker S, Meeker S, et al. Inhibition of voltage-gated K(+) currents by endothelin-1 in human pulmonary arterial myocytes. Am J Physiol Lung Cell Mol Physiol 2001;281:1115-22. https://doi.org/10.1152/ajplung.2001.281.5.L1115
  18. Wong CM, Bansal G, Pavlickova L, Marcocci L, Suzuki YJ. Reactive oxygen species and antioxidants in pulmonary hypertension. Antioxid Redox Signal 2013;18:1789-96. https://doi.org/10.1089/ars.2012.4568
  19. Konduri GG, Bakhutashvili I, Eis A, Pritchard K Jr. Oxidant stress from uncoupled nitric oxide synthase impairs vasodilation in fetal lambs with persistent pulmonary hypertension. Am J Physiol Heart Circ Physiol 2007;292:1812-20. https://doi.org/10.1152/ajpheart.00425.2006
  20. Waypa GB, Guzy R, Mungai PT, Mack MM, Marks JD, Roe MW, et al. Increases in mitochondrial reactive oxygen species trigger hypoxiainduced calcium responses in pulmonary artery smooth muscle cells. Circ Res 2006;99:970-8. https://doi.org/10.1161/01.RES.0000247068.75808.3f
  21. Weir EK, Archer SL. The mechanism of acute hypoxic pulmonary vasoconstriction: the tale of two channels. FASEB J 1995;9:183-9 https://doi.org/10.1096/fasebj.9.2.7781921
  22. Wedgwood S, Lakshminrusimha S, Czech L, Schumacker PT, Steinhorn R. Increased p22phox/Nox4 expression is involved in remodeling through hydrogen peroxide signaling in experimental persistent pulmonary hypertension of the newborn. antioxidants & redox signaling. 2013;18:1765-76. https://doi.org/10.1089/ars.2012.4766
  23. Archer SL, Marsboom G, Kim GH, Zhang HJ, Toth PT, Svensson EC, et al. Epigenetic attenuation of mitochondrial superoxide dismutase 2 in pulmonary arterial hypertension: a basis for excessive cell proliferation and a new therapeutic target. Circulation 2010;121:2661-71. https://doi.org/10.1161/CIRCULATIONAHA.109.916098
  24. Tonelli AR, Alnuaimat H, Mubarak K. Pulmonary vasodilator testing and use of calcium channel blockers in pulmonary arterial hypertension. Respir Med 2010;104:481-96. https://doi.org/10.1016/j.rmed.2009.11.015
  25. Moral-Sanz J, Mahmoud AD, Ross FA, Eldstrom J, Fedida D, Hardie DG, et al. AMP-activated protein kinase inhibit Kv1.5 channel currents of pulmonary arterial myocytes in response to hypoxia and inhibition of mitochondrial oxidative phosphorylation. J Physiol 2016;594:4901-15. https://doi.org/10.1113/JP272032
  26. Fu LC, Lv Y, Zhong Y, He Q, Liu X, Du LZ. Tyrosine phosphorylation of Kv1.5 is upregulated in intrauterine growth retardation rats with exaggerated pulmonary hypertension. Braz J Med Biol Res 2017;50:6237-43.
  27. Lv Y, Tang LL, Wei JK, Xu XF, Gu W, Fu LC, et al. Decreased Kv1.5 expression in intrauterine growth retardation rats with exaggerated pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 2013;305:856-65. https://doi.org/10.1152/ajplung.00179.2013
  28. Yuan JX, Aldinger AM, Juhasazova M, Wang J, Conte JV Jr, Gaine SP, et al. Dysfunctional voltage-gated K+ channels in pulmonary artery smooth muscle cells of patients with primary pulmonary hypertension. Circulation 1998;98:1400-6. https://doi.org/10.1161/01.CIR.98.14.1400
  29. Firth AL, Remillard CV, Platoshyn O, Fantozzi I, Ko EA, Yuan JX. Functional ion channels in human pulmonary artery smooth muscle cells: Voltage-dependent cation channels. Pulm Circ 2011;1:48-71. https://doi.org/10.4103/2045-8932.78103
  30. Yuan XJ, Wang J, Juhaszova M, Gaine SP, Rubin LJ. Attenuated K+ channel gene transcription in primary pulmonary hypertension. Lancet 1998;351:726-7. https://doi.org/10.1016/S0140-6736(05)78495-6
  31. Yuan JX, Aldinger AM, Juhaszova M, Wang J, Conte JV Jr, Gaine SP, et al. Dysfunctional voltage-gated K+ channels in pulmonary artery smooth muscle cells of patients with primary pulmonary hypertension. Circulation 1998;98:1400-6. https://doi.org/10.1161/01.CIR.98.14.1400
  32. Hibino H, Inanobe A, Furutani K, Murakami S, Findlay I, Kurachi Y. Inwardly rectifying potassium channels: their structure, function, and physiological roles. Physiol Rev 2010;90:291-366. https://doi.org/10.1152/physrev.00021.2009
  33. Ko EA, Han J, Jung ID, Park WS. Physiological roles of potassium channels in vascular smooth muscle cells. J Smooth Muscle Res 2008; 44:65-81. https://doi.org/10.1540/jsmr.44.65

Cited by

  1. Effect of Ambrisentan Therapy on the Expression of Endothelin Receptor, Endothelial Nitric Oxide Synthase and NADPH Oxidase 4 in Monocrotaline-induced Pulmonary Arterial Hypertension Rat Model vol.49, pp.9, 2018, https://doi.org/10.4070/kcj.2019.0006
  2. Potassium channels in vascular smooth muscle: a pathophysiological and pharmacological perspective vol.33, pp.5, 2018, https://doi.org/10.1111/fcp.12461
  3. Transcriptomic profile of cationic channels in human pulmonary arterial hypertension vol.11, pp.1, 2021, https://doi.org/10.1038/s41598-021-95196-z