55th Bowditch Lecture: Effects of chronic hypoxia on the pulmonary circulation: Role of HIF-1

Journal of Applied Physiology

Volumn 113, Issue 9, 2012, Pages 1343-1352

  Shimoda, Larissa A ^a  

^a JOHNS HOPKINS UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

Chronic hypoxia; Hypoxia inducible factor 1; Pulmonary hypertension

Indexed keywords

CALCIUM; HYPOXIA INDUCIBLE FACTOR 1; POTASSIUM CHANNEL;

ANIMAL; ANOXIA; ARTICLE; DRUG ANTAGONISM; HUMAN; LUNG; LUNG CIRCULATION; METABOLISM; PATHOPHYSIOLOGY; PH; PHYSIOLOGY; PULMONARY ARTERY; PULMONARY HYPERTENSION; VASCULAR SMOOTH MUSCLE;

ANIMALS; ANOXIA; CALCIUM; HUMANS; HYDROGEN-ION CONCENTRATION; HYPERTENSION, PULMONARY; HYPOXIA-INDUCIBLE FACTOR 1; LUNG; MUSCLE, SMOOTH, VASCULAR; POTASSIUM CHANNELS; PULMONARY ARTERY; PULMONARY CIRCULATION;

EID: 84875741389     PISSN: 87507587     EISSN: 15221601     Source Type: Journal    
DOI: 10.1152/japplphysiol.00843.2012     Document Type: Review

References (98)

1. Abud EM, Maylor J, Undem C, Punjabi A, Zaiman AL, Myers AC, Sylvester JT, Semenza GL, Shimoda LA. Digoxin inhibits development of hypoxic pulmonary hypertension in mice. Proc Natl Acad Sci USA 109: 1239-1244, 2012.
2. Appelhoff RJ, Tian YM, Raval RR, Turley H, Harris AL, Pugh CW, Ratcliffe PJ, Gleadle JM. Differential function of the prolyl hydroxylases PHD1, PHD2, and PHD3 in the regulation of hypoxia-inducible factor. J Biol Chem 279: 38458-38465, 2004.
3. Archer SL, Souil E, Dinh-Xuan AT, Schremmer B, Mercier JC, El Yaagoubi A, Nguyen-Huu L, Reeve HL, Hampl V. Molecular identification of the role of voltage-gated K+ channels, Kv1.5 and Kv21, in hypoxic pulmonary vasoconstriction and control of resting membrane potential in rat pulmonary artery myocytes. J Clin Invest 101: 2319-2330, 1998.
4. Attaphitaya S, Park K, Melvin JE. Molecular cloning and functional expression of a rat Na+/H+ exchanger (NHE5) highly expressed in brain. J Biol Chem 274: 4383-4388, 1999.
5. Beller GA, Smith TW, Abelmann WH, Haber E, Hood WB Jr. Digitalis intoxication. A prospective clinical study with serum level correlations. N Engl J Med 284: 989-997, 1971.
6. Berra E, Benizri E, Ginouves A, Volmat V, Roux D, Pouyssegur J. HIF prolyl-hydroxylase 2 is the key oxygen sensor setting low steady-state levels of HIF-1α in normoxia. EMBO J 22: 4082-4090, 2003.
7. Beutner A. Ueber die strom-und druckkrafte des blutes in der arteria pulmonalis. Z Rationelle Med 2: 97-138, 1852.
8. Bonnet S, Michelakis ED, Porter CJ, Andrade-Navarro MA, Thebaud B, Bonnet S, Haromy A, Harry G, Moudgil R, McMurtry MS, Weir EK, Archer SL. An abnormal mitochondrial-hypoxia inducible factor- 1α-Kv channel pathway disrupts oxygen sensing and triggers pulmonary arterial hypertension in fawn hooded rats: similarities to human pulmonary arterial hypertension. Circulation 113: 2630-2641, 2006.
9. Brant SR, Yun CH, Donowitz M, Tse CM. Cloning, tissue distribution, and functional analysis of the human Na+/H+ exchanger isoform, NHE3. Am J Physiol Cell Physiol 269: C198-C206, 1995.
10. Davies P, Maddalo F, Reid L. Effects of chronic hypoxia on structure and reactivity of rat lung microvessels. J Appl Physiol 58: 795-801, 1985.
11. Epstein AC, Gleadle JM, McNeill LA, Hewitson KS, O'Rourke J, Mole DR, Mukherji M, Metzen E, Wilson MI, Dhanda A, Tian YM, Masson N, Hamilton DL, Jaakkola P, Barstead R, Hodgkin J, Maxwell PH, Pugh CW, Schofield CJ, Ratcliffe PJC. Elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell 107: 43-54, 2001.
12. Golovina VA, Platoshyn O, Bailey CL, Wang J, Limsuwan A, Sweeney M, Rubin LJ, Yuan JX. Upregulated TRP and enhanced capacitative Ca2+ entry in human pulmonary artery myocytes during proliferation. Am J Physiol Heart Circ Physiol 280: H746-H755, 2001.
13. Green LH, Smith TW. The use of digitalis in patients with pulmonary disease. Ann Intern Med 87: 459-465, 1977.
14. Hofstetter W, Siegrist M, Simonin A, Bonny O, Fuster DG. Sodium/ hydrogen exchanger NHA2 in osteoclasts: subcellular localization and role in vitro and in vivo. Bone 47: 331-340, 2010.
15. Hong Z, Weir EK, Nelson DP, Olschewski A. Subacute hypoxia decreases voltage-activated potassium channel expression and function in pulmonary artery myocytes. Am J Respir Cell Mol Biol 31: 337-343, 2004.
16. Humbert M, Morrell NW, Archer SL, Stenmark KR, MacLean MR, Lang IM, Christman BW, Weir EK, Eickelberg O, Voelkel NF, Rabinovitch M. Cellular and molecular pathobiology of pulmonary arterial hypertension. J Am Coll Cardiol 43: 13S-24S, 2004.
17. Ivan M, Kondo K, Yang H, Kim W, Valiando J, Ohh M, Salic A, Asara JM, Lane WS, Kaelin WG Jr. HIFα targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science 292: 464-468, 2001.
18. Iyer NV, Kotch LE, Agani F, Leung SW, Laughner E, Wenger RH, Gassmann M, Gearhart JD, Lawler AM, Yu AY, Semenza GL. Cellular and developmental control of O2 homeostasis by hypoxia-inducible factor 1α. Genes Dev 12: 149-162, 1998.
19. Jaakkola P, Mole DR, Tian YM, Wilson MI, Gielbert J, Gaskell SJ, Kriegsheim A, Hebestreit HF, Mukherji M, Schofield CJ, Maxwell PH, Pugh CW, Ratcliffe PJ. Targeting of HIF-α to the von Hippel- Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science 292: 468-472, 2001.
20. Johnson DC, Joshi RC, Mehta R, Cunnington AR. Acute and long term effect of nifedipine on pulmonary hypertension secondary to chronic obstructive airways disease. Eur J Respir Dis 146: 495-502, 1986.
21. Jones K, Higenbottam T, Wallwork J. Pulmonary vasodilation with prostacyclin in primary and secondary pulmonary hypertension. Chest 96: 784-789, 1989.
22. Kelly BD, Hackett SF, Hirota K, Oshima Y, Cai Z, Berg-Dixon S, Rowan A, Yan Z, Campochiaro PA, Semenza GL. Cell type-specific regulation of angiogenic growth factor gene expression and induction of angiogenesis in nonischemic tissue by a constitutively active form of hypoxia-inducible factor 1. Circ Res 93: 1074-1081, 2003.
23. Knowles HJ, Tian YM, Mole DR, Harris AL. Novel mechanism of action for hydralazine: induction of hypoxia-inducible factor-1alpha, vascular endothelial growth factor, and angiogenesis by inhibition of prolyl hydroxylases. Circ Res 95: 162-169, 2004.
24. Kruse HJ, Bauriedel G, Heimerl J, Hofling B, Weber PC. Role of L-type calcium channels on stimulated calcium influx and on proliferative activity of human coronary smooth muscle cells. J Cardiovasc Pharmacol 24: 328-335, 1994.
25. Leach RM, Sheehan DW, Chacko VP, Sylvester JT. Energy state, pH, and vasomotor tone during hypoxia in precontracted pulmonary and femoral arteries. Am J Physiol Lung Cell Mol Physiol 278: L294-L304, 2000.
26. Lee K, Zhang H, Qian DZ, Rey S, Liu JO, Semenza GL. Acriflavine inhibits HIF-1 dimerization, tumor growth, and vascularization. Proc Natl Acad Sci USA 106: 17910-17915, 2009.
27. Lee YM, Jeong CH, Koo SY, Son MJ, Song HS, Bae SK, Raleigh JA, Chung HY, Yoo MA, Kim KW. Determination of hypoxic region by hypoxia marker in developing mouse embryos in vivo: a possible signal for vessel development. Dev Dyn 220: 175-186, 2001.
28. Leggett K, Maylor J, Undem C, Lai N, Lu W, Schweitzer KS, King LS, Myers AC, Sylvester JT, Sidhaye VK, Shimoda LA. Hypoxiainduced migration in pulmonary arterial smooth muscle cells requires calcium-dependent upregulation of aquaporin 1. Am J Physiol Lung Cell Mol Physiol 303: L343-L353, 2012.
29. Lin MJ, Leung GP, Zhang WM, Yang XR, Yip KP, Tse CM, Sham JS. Chronic hypoxia-induced upregulation of store-operated and receptor-operated Ca2+ channels in pulmonary arterial smooth muscle cells: a novel mechanism of hypoxic pulmonary hypertension. Circ Res 95: 496-505, 2004.
30. Lu W, Wang J, Peng G, Shimoda LA, Sylvester JT. Knockdown of stromal interaction molecule 1 attenuates store-operated Ca2+ entry and Ca2+ responses to acute hypoxia in pulmonary arterial smooth muscle. Am J Physiol Lung Cell Mol Physiol 297: L17-L25, 2009.
31. Lu W, Wang J, Shimoda LA, Sylvester JT. Differences in STIM1 and TRPC expression in proximal and distal pulmonary arterial smooth muscle are associated with differences in Ca2+ responses to hypoxia. Am J Physiol Lung Cell Mol Physiol 295: L104-L113, 2008.
32. Madden JA, Ray DE, Keller PA, Kleinman JG. Ion exchange activity in pulmonary artery smooth muscle cells: the response to hypoxia. Am J Physiol Lung Cell Mol Physiol 280: L264-L271, 2001.
33. Mahon PC, Hirota K, Semenza GL. FIH-1: a novel protein that interacts with HIF-1α and VHL to mediate repression of HIF-1 transcriptional activity. Genes Dev 15: 2675-2686, 2001.
34. Masson N, Willam C, Maxwell PH, Pugh CW, Ratcliffe PJ. Independent function of two destruction domains in hypoxia-inducible factor-α chains activated by prolyl hydroxylation. EMBO J 20: 5197-5206, 2001.
35. McLaughlin VV, Rich S. Pulmonary hypertension. Curr Probl Cardiol 29: 575-634, 2004.
36. McMahon S, Charbonneau M, Grandmont S, Richard DE, Dubois CM. Transforming growth factor β1 induces hypoxia-inducible factor-1 stabilization through selective inhibition of PHD2 expression. J Biol Chem 281: 24171-24181, 2006.
37. McMurtry IF, Davidson AB, Reeves JT, Grover RF. Inhibition of hypoxic pulmonary vasoconstriction by calcium antagonists in isolated rat lungs. Circ Res 38: 99-104, 1976.
38. Metzen E, Berchner-Pfannschmidt U, Stengel P, Marxsen JH, Stolze I, Klinger M, Huang WQ, Wotzlaw C, Hellwig-Burgel T, Jelkmann W, Acker H, Fandrey J. Intracellular localisation of human HIF-1α hydroxylases: implications for oxygen sensing. J Cell Sci 116: 1319-1326, 2003.
39. Meyrick B, Reid L. The effect of continued hypoxia on rat pulmonary arterial circulation. An ultrastructural study. Lab Invest 38: 188-200, 1978.
40. Miyazaki E, Sakaguchi M, Wakabayashi S, Shigekawa M, Mihara K. NHE6 protein possesses a signal peptide destined for endoplasmic reticulum membrane and localizes in secretory organelles of the cell. J Biol Chem 276: 49221-49227, 2001.
41. Moinard J, Manier G, Pillet O, Castaing Y. Effect of inhaled nitric oxide on hemodynamics and VA/Q inequalities in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 149: 1482-1487, 1994.
42. Morrell NW, Adnot S, Archer SL, Dupuis J, Jones PL, MacLean MR, McMurtry IF, Stenmark KR, Thistlethwaite PA, Weissmann N, Yuan JX, Weir EK. Cellular and molecular basis of pulmonary arterial hypertension. J Am Coll Cardiol 54: S20-31, 2009.
43. Nagaoka T, Fagan KA, Gebb SA, Morris KG, Suzuki T, Shimokawa H, McMurtry IF, Oka M. Inhaled Rho kinase inhibitors are potent and selective vasodilators in rat pulmonary hypertension. Am J Respir Crit Care Med 171: 494-499, 2005.
44. Nakamura N, Tanaka S, Teko Y, Mitsui K, Kanazawa H. Four Na+/H+ exchanger isoforms are distributed to Golgi and post-Golgi compartments and are involved in organelle pH regulation. J Biol Chem 280: 1561-1572, 2005.
45. Ng LC, Ramduny D, Airey JA, Singer CA, Keller PS, Shen XM, Tian H, Valencik M, Hume JR. Orai1 interacts with STIM1 and mediates capacitative Ca2+ entry in mouse pulmonary arterial smooth muscle cells. Am J Physiol Cell Physiol 299: C1079-C1090, 2010.
46. Numata M, Orlowski J. Molecular cloning and characterization of a novel (Na-, K+)/H- exchanger localized to the trans-Golgi network. J Biol Chem 276: 17387-17394, 2001.
47. Numata M, Petrecca K, Lake N, Orlowski J. Identification of a mitochondrial Na+/H+ exchanger. J Biol Chem 273: 6951-6959, 1998.
48. Oka M, Morris KG, McMurtry IF. NIP-121 is more effective than nifedipine in acutely reversing chronic pulmonary hypertension. J Appl Physiol 75: 1075-1080, 1993.
49. Orlowski J, Kandasamy RA, Shull GE. Molecular cloning of putative members of the Na/H exchanger gene family. cDNA cloning, deduced amino acid sequence, and mRNA tissue expression of the rat Na/H exchanger NHE-1 and two structurally related proteins. J Biol Chem 267: 9331-9339, 1992.
50. Phillips RJ, Mestas J, Gharaee-Kermani M, Burdick MD, Sica A, Belperio JA, Keane MP, Strieter RM. Epidermal growth factor and hypoxia-induced expression of CXC chemokine receptor 4 on non-small cell lung cancer cells is regulated by the phosphatidylinositol 3-kinase/ PTEN/AKT/mammalian target of rapamycin signaling pathway and activation of hypoxia inducible factor-1α. J Biol Chem 280: 22473-22481, 2005.
51. Pisarcik S, Sylvester JT, Semenza GL, Shimoda LA. Endothelin-1 (ET-1) induces hypoxia-inducible factor 1 (HIF-1) in pulmonary arterial smooth muscle cells (PASMCs). FASEB J 22: 1209.1222, 2008.
52. Pozeg ZI, Michelakis ED, McMurtry MS, Thebaud B, Wu XC, Dyck JR, Hashimoto K, Wang S, Moudgil R, Harry G, Sultanian R, Koshal A, Archer SL. In vivo gene transfer of the O2-sensitive potassium channel Kv1.5 reduces pulmonary hypertension and restores hypoxic pulmonary vasoconstriction in chronically hypoxic rats. Circulation 107: 2037-2044, 2003.
53. Quinn DA, Dahlberg CG, Bonventre JP, Scheid CR, Honeyman T, Joseph PM, Thompson BT, Hales CA. The role of Na+/H+ exchange and growth factors in pulmonary artery smooth muscle cell proliferation. Am J Respir Cell Mol Biol 14: 139-145, 1996.
54. Quinn DA, Du HK, Thompson BT, Hales CA. Amiloride analogs inhibit chronic hypoxic pulmonary hypertension. Am J Respir Crit Care Med 157: 1263-1268, 1998.
55. Quinn DA, Honeyman TW, Joseph PM, Thompson BT, Hales CA, Scheid CR. Contribution of Na+/H+ exchange to pH regulation in pulmonary artery smooth muscle cells. Am J Respir Cell Mol Biol 5: 586-591, 1991.
56. Rich S, Seidlitz M, Dodin E, Osimani D, Judd D, Genthner D, McLaughlin V, Francis G. The short-term effects of digoxin in patients with right ventricular dysfunction from pulmonary hypertension. Chest 114: 787-792, 1998.
57. Richard DE, Berra E, Pouyssegur J. Nonhypoxic pathway mediates the induction of hypoxia-inducible factor 1α in vascular smooth muscle cells. J Biol Chem 275: 26765-26771, 2000.
58. Rios EJ, Fallon M, Wang J, Shimoda LA. Chronic hypoxia elevates intracellular pH and activates Na+/H+ exchange in pulmonary arterial smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 289: L867-L874, 2005.
59. Rodman DM, Yamaguchi T, O'Brien RF, McMurtry IF. Hypoxic contraction of isolated rat pulmonary artery. J Pharmacol Exp Ther 248: 952-959, 1989.
60. Salvaterra CG, Goldman WF. Acute hypoxia increases cytosolic calcium in cultured pulmonary arterial myocytes. Am J Physiol Lung Cell Mol Physiol 264: L323-L328, 1993.
61. Semenza GL. Hypoxia-inducible factors in physiology and medicine. Cell 148: 399-408, 2012.
62. Semenza GL. Regulation of oxygen homeostasis by hypoxia-inducible factor 1. Physiology 24: 97-106, 2009.
63. Semenza GL, Wang GL. A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation. Mol Cell Biol 12: 5447-5454, 1992.
64. Seshadri V, Fox PL, Mukhopadhyay CK. Dual role of insulin in transcriptional regulation of the acute phase reactant ceruloplasmin. J Biol Chem 277: 27903-27911, 2002.
65. Shimoda LA, Fallon M, Pisarcik S, Wang J, Semenza GL. HIF-1 regulates hypoxic induction of NHE1 expression and alkalinization of intracellular pH in pulmonary arterial myocytes. Am J Physiol Lung Cell Mol Physiol 291: L941-L949, 2006.
66. Shimoda LA, Manalo DJ, Sham JS, Semenza GL, Sylvester JT. Partial HIF-1α deficiency impairs pulmonary arterial myocyte electrophysiological responses to hypoxia. Am J Physiol Lung Cell Mol Physiol 281: L202-L208, 2001.
67. Shimoda LA, Sham JS, Shimoda TH, Sylvester JT. L-type Ca2+ channels, resting [Ca2+]i, and ET-1-induced responses in chronically hypoxic pulmonary myocytes. Am J Physiol Lung Cell Mol Physiol 279: L884-L894, 2000.
68. Smirnov SV, Robertson TP, Ward JP, Aaronson PI. Chronic hypoxia is associated with reduced delayed rectifier K+ current in rat pulmonary artery muscle cells. Am J Physiol Heart Circ Physiol 266: H365-H370, 1994.
69. Spinella F, Rosano L, Di Castro V, Decandia S, Nicotra MR, Natali PG, Bagnato A. Endothelin-1 and endothelin-3 promote invasive behavior via hypoxia-inducible factor-1α in human melanoma cells. Cancer Res 67: 1725-1734, 2007.
70. Spinella F, Rosano L, Di Castro V, Natali PG, Bagnato A. Endothelin-1 induces vascular endothelial growth factor by increasing hypoxia-inducible factor-1α in ovarian carcinoma cells. J Biol Chem 277: 27850-27855, 2002.
71. Stenmark KR, McMurtry IF. Vascular remodeling versus vasoconstriction in chronic hypoxic pulmonary hypertension: a time for reappraisal? Circ Res 97: 95-98, 2005.
72. Stenmark KR, Meyrick B, Galie N, Mooi WJ, McMurtry IF. Animal models of pulmonary arterial hypertension: the hope for etiological discovery and pharmacological cure. Am J Physiol Lung Cell Mol Physiol 297: L1013-L1032, 2009.
73. Suzuki H, Twarog BM. Membrane properties of smooth muscle cells in pulmonary hypertensive rats. Am J Physiol Heart Circ Physiol 242: H907-H915, 1982.
74. Sweeney M, Yu Y, Platoshyn O, Zhang S, McDaniel SS, Yuan JX. Inhibition of endogenous TRP1 decreases capacitative Ca2+ entry and attenuates pulmonary artery smooth muscle cell proliferation. Am J Physiol Lung Cell Mol Physiol 283: L144-L155, 2002.
75. Sylvester JT, Shimoda LA, Aaronson PI, Ward JP. Hypoxic pulmonary vasoconstriction. Physiol Rev 92: 367-520, 2012.
76. Tagaito Y, Polotsky VY, Campen MJ, Wilson JA, Balbir A, Smith PL, Schwartz AR, O'Donnell CP. A model of sleep-disordered breathing in the C57BL/6J mouse. J Appl Physiol 91: 2758-2766, 2001.
77. Treins C, Giorgetti-Peraldi S, Murdaca J, Monthouel-Kartmann MN, Van Obberghen E. Regulation of hypoxia-inducible factor (HIF)-1 activity and expression of HIF hydroxylases in response to insulin-like growth factor I. Mol Endocrinol 19: 1304-1317, 2005.
78. Treins C, Giorgetti-Peraldi S, Murdaca J, Semenza GL, Van Obberghen E. Insulin stimulates hypoxia-inducible factor 1 through a phosphatidylinositol 3-kinase/target of rapamycin-dependent signaling pathway. J Biol Chem 277: 27975-27981, 2002.
79. Tuder RM, Chacon M, Alger L, Wang J, Taraseviciene-Stewart L, Kasahara Y, Cool CD, Bishop AE, Geraci M, Semenza GL, Yacoub M, Polak JM, Voelkel NF. Expression of angiogenesis-related molecules in plexiform lesions in severe pulmonary hypertension: evidence for a process of disordered angiogenesis. J Pathol 195: 367-374, 2001.
80. Voelkel NF, Tuder RM. Hypoxia-induced pulmonary vascular remodeling: a model for what human disease? J Clin Invest 106: 733-738, 2000.
81. von Euler U, Liljestrand G. Observations on the pulmonary arterial blood pressure of the cat. Acta Physiol (Oxf) 12: 301-320, 1946.
82. Wang J, Juhaszova M, Rubin LJ, Yuan XJ. Hypoxia inhibits gene expression of voltage-gated K+ channel - subunits in pulmonary artery smooth muscle cells. J Clin Invest 100: 2347-2353, 1997.
83. Wang J, Shimoda LA, Sylvester JT. Capacitative calcium entry and TRPC channel proteins are expressed in rat distal pulmonary arterial smooth muscle. Am J Physiol Lung Cell Mol Physiol 286: L848-L858, 2004.
84. Wang J, Weigand L, Lu W, Sylvester JT, Semenza GL, Shimoda LA. Hypoxia inducible factor 1 mediates hypoxia-induced TRPC expression and elevated intracellular Ca2+ in pulmonary arterial smooth muscle cells. Circ Res 98: 1528-1537, 2006.
85. Wang J, Weigand L, Wang W, Sylvester JT, Shimoda LA. Chronic hypoxia inhibits Kv channel gene expression in rat distal pulmonary artery. Am J Physiol Lung Cell Mol Physiol 288: L1049-L1058, 2005.
86. Wang Z, Orlowski J, Shull GE. Primary structure and functional expression of a novel gastrointestinal isoform of the rat Na/H exchanger. J Biol Chem 268: 11925-11928, 1993.
87. Weigand L, Foxson J, Wang J, Shimoda LA, Sylvester JT. Inhibition of hypoxic pulmonary vasoconstriction by antagonists of store-operated Ca2+ and nonselective cation channels. Am J Physiol Lung Cell Mol Physiol 289: L5-L13, 2005.
88. Whitman EM, Pisarcik S, Luke T, Fallon M, Wang J, Sylvester JT, Semenza GL, Shimoda LA. Endothelin-1 mediates hypoxia-induced inhibition of voltage-gated K+ channel expression in pulmonary arterial myocytes. Am J Physiol Lung Cell Mol Physiol 294: L309-L318, 2008.
89. Wiener CM, Booth G, Semenza GL. In vivo expression of mRNAs encoding hypoxia-inducible factor 1. Biochem Biophys Res Commun 225: 485-488, 1996.
90. Yoshida T, Zhang H, Iwase T, Shen J, Semenza GL, Campochiaro PA. Digoxin inhibits retinal ischemia-induced HIF-1α expression and ocular neovascularization. FASEB J 24(6): 1759-1767, 2010.
91. Yu AY, Frid MG, Shimoda LA, Wiener CM, Stenmark K, Semenza GL. Temporal, spatial, and oxygen-regulated expression of hypoxiainducible factor-1 in the lung. Am J Physiol Lung Cell Mol Physiol 275: L818-L826, 1998.
92. Yu AY, Shimoda LA, Iyer NV, Huso DL, Sun X, McWilliams R, Beaty T, Sham JS, Wiener CM, Sylvester JT, Semenza GL. Impaired physiological responses to chronic hypoxia in mice partially deficient for hypoxia-inducible factor 1α. J Clin Invest 103: 691-696, 1999.
93. Yu F, White SB, Zhao Q, Lee FS. HIF-1alpha binding to VHL is regulated by stimulus-sensitive proline hydroxylation. Proc Natl Acad Sci USA 98: 9630-9635, 2001.
94. Yu L, Quinn DA, Garg HG, Hales CA. Deficiency of the NHE1 gene prevents hypoxia-induced pulmonary hypertension and vascular remodeling. Am J Respir Crit Care Med 177: 1276-1284, 2008.
95. Yu Y, Sweeney M, Zhang S, Platoshyn O, Landsberg J, Rothman A, Yuan JX. PDGF stimulates pulmonary vascular smooth muscle cell proliferation by upregulating TRPC6 expression. Am J Physiol Cell Physiol 284: C316-C330, 2003.
96. Yuan XJ. Voltage-gated K+ currents regulate resting membrane potential and [Ca2+]i in pulmonary arterial myocytes. Circ Res 77: 370-378, 1995.
97. Zelzer E, Levy Y, Kahana C, Shilo BZ, Rubinstein M, Cohen B. Insulin induces transcription of target genes through the hypoxia-inducible factor HIF-1α/ARNT. EMBO J 17: 5085-5094, 1998.
98. Zhang H, Qian DZ, Tan YS, Lee K, Gao P, Ren YR, Rey S, Hammers H, Chang D, Pili R, Dang CV, Liu JO, Semenza GL. Digoxin and other cardiac glycosides inhibit HIF-1α synthesis and block tumor growth. Proc Natl Acad Sci USA 105: 19579-19586, 2008.