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NADPH oxidases—do they play a role in TRPC regulation under hypoxia?

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Abstract

In the lung, acute alveolar hypoxia causes hypoxic pulmonary vasoconstriction (HPV) to maintain ventilation perfusion matching and thus optimal oxygenation of blood. In contrast, global chronic hypoxia triggers a pathological thickening of pulmonary arterial walls, called pulmonary vascular remodelling, leading to persistence of pulmonary hypertension (PH). Moreover, ischaemia or hypoxia can lead to a damage of pulmonary endothelial cells with subsequent oedema formation. Alterations in reactive oxygen species (ROS) have been suggested as a crucial mediator of such responses. Among the various sources of cellular ROS production, NADPH oxidases (NOXs) have been found to contribute to these physiological and pathophysiological signalling processes. NOXs are the only known examples that generate ROS as the primary function of the enzyme system. However, the downstream targets of NOX-derived ROS signalling in hypoxia are still not known. Canonical transient receptor potential (TRPC) channels recently have been recognised as directly or indirectly ROS-activated channels and have been shown to be essential for hypoxia-dependent vascular regulatory processes in the lung. Against this background, we here summarise the current knowledge on NOX-mediated TRPC channel signalling during hypoxia in the pulmonary circulation.

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References

  1. Aaronson PI (2006) TRPC channel upregulation in chronically hypoxic pulmonary arteries: the HIF-1 bandwagon gathers steam. Circ Res 98:1465–1467. doi:10.1161/01.RES.0000231254.58548.b4

    Article  PubMed  CAS  Google Scholar 

  2. Aarts M, Iihara K, Wei W-L, Xiong Z-G, Arundine M, Cerwinski W, MacDonald JF, Tymianski M (2003) A key role for TRPM7 channels in anoxic neuronal death. Cell 115:863–877

    Article  PubMed  CAS  Google Scholar 

  3. Adesina SE, Kang BY, Bijli KM, Ma J, Cheng J, Murphy T, Michael Hart C, Sutliff RL (2015) Targeting mitochondrial reactive oxygen species to modulate hypoxia-induced pulmonary hypertension. Free Radic Biol Med. doi:10.1016/j.freeradbiomed.2015.05.042

    Google Scholar 

  4. Ahmad M, Kelly MR, Zhao X, Kandhi S, Wolin MS (2010) Roles for Nox4 in the contractile response of bovine pulmonary arteries to hypoxia. Am J Physiol Heart Circ Physiol 298:H1879–H1888. doi:10.1152/ajpheart.01228.2009

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Ali MH, Schlidt SA, Chandel NS, Hynes KL, Schumacker PT, Gewertz BL (1999) Endothelial permeability and IL-6 production during hypoxia: role of ROS in signal transduction. Am J Physiol 277:L1057–L1065

    PubMed  CAS  Google Scholar 

  6. Altenhofer S, Kleikers PW, Radermacher KA, Scheurer P, Rob Hermans JJ, Schiffers P, Ho H, Wingler K, Schmidt HH (2012) The NOX toolbox: validating the role of NADPH oxidases in physiology and disease. Cell Mol Life Sci : CMLS 69:2327–2343. doi:10.1007/s00018-012-1010-9

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Alzoubi A, Almalouf P, Toba M, O'Neill K, Qian X, Francis M, Taylor MS, Alexeyev M, McMurtry IF, Oka M, Stevens T (2013) TRPC4 inactivation confers a survival benefit in severe pulmonary arterial hypertension. Am J Pathol 183:1779–1788. doi:10.1016/j.ajpath.2013.08.016

    Article  PubMed  CAS  Google Scholar 

  8. Archer SL, Huang J, Henry T, Peterson D, Weir EK (1993) A redox-based O2 sensor in rat pulmonary vasculature. Circ Res 73:1100–1112

    Article  PubMed  CAS  Google Scholar 

  9. Archer SL, Reeve HL, Michelakis E, Puttagunta L, Waite R, Nelson DP, Dinauer MC, Weir EK (1999) O2 sensing is preserved in mice lacking the gp91 phox subunit of NADPH oxidase. Proc Natl Acad Sci U S A 96:7944–7949

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Archer SL, Gomberg-Maitland M, Maitland ML, Rich S, Garcia JG, Weir EK (2008) Mitochondrial metabolism, redox signaling, and fusion: a mitochondria-ROS-HIF-1alpha-Kv1.5 O2-sensing pathway at the intersection of pulmonary hypertension and cancer. Am J Physiol Heart Circ Physiol 294:H570–H578. doi:10.1152/ajpheart.01324.2007

    Article  PubMed  CAS  Google Scholar 

  11. Archer SL, Weir EK, Wilkins MR (2010) Basic science of pulmonary arterial hypertension for clinicians: new concepts and experimental therapies. Circulation 121:2045–2066. doi:10.1161/CIRCULATIONAHA.108.847707

    Article  PubMed  PubMed Central  Google Scholar 

  12. Arnelle DR, Stamler JS (1995) NO+, NO, and NO− donation by S-nitrosothiols: implications for regulation of physiological functions by S-nitrosylation and acceleration of disulfide formation. Arch Biochem Biophys 318:279–285. doi:10.1006/abbi.1995.1231

    Article  PubMed  CAS  Google Scholar 

  13. Ascenzi P, di Masi A, Sciorati C, Clementi E (2010) Peroxynitrite—an ugly biofactor? Biofactors 36:264–273. doi:10.1002/biof.103

    Article  PubMed  CAS  Google Scholar 

  14. Balzer M, Lintschinger B, Groschner K (1999) Evidence for a role of Trp proteins in the oxidative stress-induced membrane conductances of porcine aortic endothelial cells. Cardiovasc Res 42:543–549

    Article  PubMed  CAS  Google Scholar 

  15. Banfi B, Tirone F, Durussel I, Knisz J, Moskwa P, Molnar GZ, Krause KH, Cox JA (2004) Mechanism of Ca2+ activation of the NADPH oxidase 5 (NOX5). J Biol Chem 279:18583–18591. doi:10.1074/jbc.M310268200

    Article  PubMed  CAS  Google Scholar 

  16. Bannister JP, Young BA, Main MJ, Sivaprasadarao A, Wray D (1999) The effects of oxidizing and cysteine-reactive reagents on the inward rectifier potassium channels Kir2.3 and Kir1.1. Arch Eur J Physiol 438:868–878

    Article  CAS  Google Scholar 

  17. Becker LB (2004) New concepts in reactive oxygen species and cardiovascular reperfusion physiology. Cardiovasc Res 61:461–470. doi:10.1016/j.cardiores.2003.10.025

    Article  PubMed  CAS  Google Scholar 

  18. Bedard K, Krause KH (2007) The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology. Physiol Rev 87:245–313. doi:10.1152/physrev.00044.2005

    Article  PubMed  CAS  Google Scholar 

  19. Beech DJ, Xu SZ, McHugh D, Flemming R (2003) TRPC1 store-operated cationic channel subunit. Cell Calcium 33:433–440

    Article  PubMed  CAS  Google Scholar 

  20. Bernard K, Hecker L, Luckhardt TR, Cheng G, Thannickal VJ (2014) NADPH oxidases in lung health and disease. Antioxid Redox Signal 20:2838–2853. doi:10.1089/ars.2013.5608

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Bogeski I, Kappl R, Kummerow C, Gulaboski R, Hoth M, Niemeyer BA (2011) Redox regulation of calcium ion channels: chemical and physiological aspects. Cell Calcium 50:407–423. doi:10.1016/j.ceca.2011.07.006

    Article  PubMed  CAS  Google Scholar 

  22. 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 (2006) An abnormal mitochondrial-hypoxia inducible factor-1alpha-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. doi:10.1161/CIRCULATIONAHA.105.609008

    Article  PubMed  CAS  Google Scholar 

  23. Brandes RP (2010) Vascular functions of NADPH oxidases. Hypertension 56:17–21. doi:10.1161/HYPERTENSIONAHA.108.120295

    Article  PubMed  CAS  Google Scholar 

  24. Brandes RP, Kreuzer J (2005) Vascular NADPH oxidases: molecular mechanisms of activation. Cardiovasc Res 65:16–27. doi:10.1016/j.cardiores.2004.08.007

    Article  PubMed  CAS  Google Scholar 

  25. Brandes RP, Weissmann N, Schroder K (2010) NADPH oxidases in cardiovascular disease. Free Radic Biol Med 49:687–706. doi:10.1016/j.freeradbiomed.2010.04.030

    Article  PubMed  CAS  Google Scholar 

  26. Brandes RP, Weissmann N, Schroder K (2014) Nox family NADPH oxidases in mechano-transduction: mechanisms and consequences. Antioxid Redox Signal 20:887–898. doi:10.1089/ars.2013.5414

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Brennan LA, Steinhorn RH, Wedgwood S, Mata-Greenwood E, Roark EA, Russell JA, Black SM (2003) Increased superoxide generation is associated with pulmonary hypertension in fetal lambs: a role for NADPH oxidase. Circ Res 92:683–691. doi:10.1161/01.RES.0000063424.28903.BB

    Article  PubMed  CAS  Google Scholar 

  28. Case AJ, Li S, Basu U, Tian J, Zimmerman MC (2013) Mitochondrial-localized NADPH oxidase 4 is a source of superoxide in angiotensin II-stimulated neurons. Am J Physiol Heart Circ Physiol 305:H19–H28. doi:10.1152/ajpheart.00974.2012

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Chandel NS (2010) Mitochondrial regulation of oxygen sensing. Adv Exp Med Biol 661:339–354. doi:10.1007/978-1-60761-500-2_22

    Article  PubMed  CAS  Google Scholar 

  30. Chandel NS, McClintock DS, Feliciano CE, Wood TM, Melendez JA, Rodriguez AM, Schumacker PT (2000) Reactive oxygen species generated at mitochondrial complex III stabilize hypoxia-inducible factor-1alpha during hypoxia: a mechanism of O2 sensing. J Biol Chem 275:25130–25138. doi:10.1074/jbc.M001914200

    Article  PubMed  CAS  Google Scholar 

  31. Chen YF, Feng JA, Li P, Xing D, Zhang Y, Serra R, Ambalavanan N, Majid-Hassan E, Oparil S (2006) Dominant negative mutation of the TGF-beta receptor blocks hypoxia-induced pulmonary vascular remodeling. J Appl Physiol 100:564–571. doi:10.1152/japplphysiol.00595.2005

    Article  PubMed  CAS  Google Scholar 

  32. Chen K, Kirber MT, Xiao H, Yang Y, Keaney JF Jr (2008) Regulation of ROS signal transduction by NADPH oxidase 4 localization. J Cell Biol 181:1129–1139. doi:10.1083/jcb.200709049

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Chen X, Chen H, Deng R, Shen J (2014) Pros and cons of current approaches for detecting peroxynitrite and their applications. Biomed J 37:120–126. doi:10.4103/2319-4170.134084

    Article  PubMed  CAS  Google Scholar 

  34. Choi DH, Cristovao AC, Guhathakurta S, Lee J, Joh TH, Beal MF, Kim YS (2012) NADPH oxidase 1-mediated oxidative stress leads to dopamine neuron death in Parkinson’s disease. Antioxid Redox Signal 16:1033–1045. doi:10.1089/ars.2011.3960

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Choi S, Maleth J, Jha A, Lee KP, Kim MS, So I, Ahuja M, Muallem S (2014) The TRPCs-STIM1-Orai interaction. Handb Exp Pharmacol 223:1035–1054. doi:10.1007/978-3-319-05161-1_13

    Article  PubMed  CAS  Google Scholar 

  36. Cioffi DL (2011) Redox regulation of endothelial canonical transient receptor potential channels. Antioxid Redox Signal 15:1567–1582. doi:10.1089/ars.2010.3740

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Coppock EA, Martens JR, Tamkun MM (2001) Molecular basis of hypoxia-induced pulmonary vasoconstriction: role of voltage-gated K+ channels. Am J Physiol Lung Cell Mol Physiol 281:L1–L12

    PubMed  CAS  Google Scholar 

  38. D'Autreaux B, Toledano MB (2007) ROS as signalling molecules: mechanisms that generate specificity in ROS homeostasis. Nat Rev Mol Cell Biol 8:813–824. doi:10.1038/nrm2256

    Article  PubMed  CAS  Google Scholar 

  39. Dennis KE, Aschner JL, Milatovic D, Schmidt JW, Aschner M, Kaplowitz MR, Zhang Y, Fike CD (2009) NADPH oxidases and reactive oxygen species at different stages of chronic hypoxia-induced pulmonary hypertension in newborn piglets. Am J Physiol Lung Cell Mol Physiol 297:L596–L607. doi:10.1152/ajplung.90568.2008

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Diebold I, Petry A, Hess J, Gorlach A (2010) The NADPH oxidase subunit NOX4 is a new target gene of the hypoxia-inducible factor-1. Mol Biol Cell 21:2087–2096. doi:10.1091/mbc.E09-12-1003

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Diebold I, Petry A, Burger M, Hess J, Görlach A (2011) NOX4 mediates activation of FoxO3a and matrix metalloproteinase-2 expression by urotensin-II. Mol Biol Cell 22:4424–4434. doi:10.1091/mbc.E10-12-0971

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Dietrich A, Mederos y Schnitzler M, Emmel J, Kalwa H, Hofmann T, Gudermann T (2003) N-linked protein glycosylation is a major determinant for basal TRPC3 and TRPC6 channel activity. J Biol Chem 278:47842–47852. doi:10.1074/jbc.M302983200

    Article  PubMed  CAS  Google Scholar 

  43. Dietrich A, Kalwa H, Fuchs B, Grimminger F, Weissmann N, Gudermann T (2007) In vivo TRPC functions in the cardiopulmonary vasculature. Cell Calcium 42:233–244. doi:10.1016/j.ceca.2007.02.009

    Article  PubMed  CAS  Google Scholar 

  44. Dietrich A, Kalwa H, Storch U, Mederos y Schnitzler M, Salanova B, Pinkenburg O, Dubrovska G, Essin K, Gollasch M, Birnbaumer L, Gudermann T (2007) Pressure-induced and store-operated cation influx in vascular smooth muscle cells is independent of TRPC1. Arch Eur J Physiol 455:465–477. doi:10.1007/s00424-007-0314-3

    Article  CAS  Google Scholar 

  45. Dietrich A, Fahlbusch M, Gudermann T (2014) Classical transient receptor potential 1 (TRPC1): channel or channel regulator? Cells 3:939–962. doi:10.3390/cells3040939

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Dikalov S, Griendling KK, Harrison DG (2007) Measurement of reactive oxygen species in cardiovascular studies. Hypertension 49:717–727. doi:10.1161/01.HYP.0000258594.87211.6b

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Djordjevic T, Pogrebniak A, BelAiba RS, Bonello S, Wotzlaw C, Acker H, Hess J, Gorlach A (2005) The expression of the NADPH oxidase subunit p22phox is regulated by a redox-sensitive pathway in endothelial cells. Free Radic Biol Med 38:616–630. doi:10.1016/j.freeradbiomed.2004.09.036

    Article  PubMed  CAS  Google Scholar 

  48. Drummond GR, Sobey CG (2014) Endothelial NADPH oxidases: which NOX to target in vascular disease? Trends Endocrinol Metab: TEM 25:452–463. doi:10.1016/j.tem.2014.06.012

    Article  PubMed  CAS  Google Scholar 

  49. Du W, Frazier M, McMahon TJ, Eu JP (2005) Redox activation of intracellular calcium release channels (ryanodine receptors) in the sustained phase of hypoxia-induced pulmonary vasoconstriction. Chest 128:556S–558S. doi:10.1378/chest.128.6_suppl.556S

    Article  PubMed  CAS  Google Scholar 

  50. Du J, Ma X, Shen B, Huang Y, Birnbaumer L, Yao X (2014) TRPV4, TRPC1, and TRPP2 assemble to form a flow-sensitive heteromeric channel. FASEB J Off Pub Fed Am Soc Exp Biol 28:4677–4685. doi:10.1096/fj.14-251652

    CAS  Google Scholar 

  51. Eder P, Molkentin JD (2011) TRPC channels as effectors of cardiac hypertrophy. Circ Res 108:265–272. doi:10.1161/CIRCRESAHA.110.225888

    Article  PubMed  CAS  Google Scholar 

  52. Enyedi B, Zana M, Donko A, Geiszt M (2013) Spatial and temporal analysis of NADPH oxidase-generated hydrogen peroxide signals by novel fluorescent reporter proteins. Antioxid Redox Signal 19:523–534. doi:10.1089/ars.2012.4594

    Article  PubMed  CAS  Google Scholar 

  53. Frank D, Johnson J, Caestecker M (2005) Bone morphogenetic protein 4 promotes vascular remodeling in hypoxic pulmonary hypertension. Chest 128:590S–591S. doi:10.1378/chest.128.6_suppl.590S

    Article  PubMed  Google Scholar 

  54. Frazziano G, Moreno L, Moral-Sanz J, Menendez C, Escolano L, Gonzalez C, Villamor E, Alvarez-Sala JL, Cogolludo AL, Perez-Vizcaino F (2011) Neutral sphingomyelinase, NADPH oxidase and reactive oxygen species. Role in acute hypoxic pulmonary vasoconstriction. J Cell Physiol 226:2633–2640. doi:10.1002/jcp.22611

    Article  PubMed  CAS  Google Scholar 

  55. Freichel M, Suh SH, Pfeifer A, Schweig U, Trost C, Weissgerber P, Biel M, Philipp S, Freise D, Droogmans G, Hofmann F, Flockerzi V, Nilius B (2001) Lack of an endothelial store-operated Ca2+ current impairs agonist-dependent vasorelaxation in TRP4−/− mice. Nat Cell Biol 3:121–127. doi:10.1038/35055019

    Article  PubMed  CAS  Google Scholar 

  56. Fuchs B, Dietrich A, Gudermann T, Kalwa H, Grimminger F, Weissmann N (2010) The role of classical transient receptor potential channels in the regulation of hypoxic pulmonary vasoconstriction. Adv Exp Med Biol 661:187–200. doi:10.1007/978-1-60761-500-2_12

    Article  PubMed  CAS  Google Scholar 

  57. Fuchs B, Sommer N, Dietrich A, Schermuly RT, Ghofrani HA, Grimminger F, Seeger W, Gudermann T, Weissmann N (2010) Redox signaling and reactive oxygen species in hypoxic pulmonary vasoconstriction. Respir Physiol Neurobiol 174:282–291. doi:10.1016/j.resp.2010.08.013

    Article  PubMed  CAS  Google Scholar 

  58. Fulton DJ (2009) Nox5 and the regulation of cellular function. Antioxid Redox Signal 11:2443–2452. doi:10.1089/ARS.2009.2587

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Gardner PR (1997) Superoxide-driven aconitase FE-S center cycling. Biosci Rep 17:33–42

    Article  PubMed  CAS  Google Scholar 

  60. Gervásio OL, Whitehead NP, Yeung EW, Phillips WD, Allen DG (2008) TRPC1 binds to caveolin-3 and is regulated by Src kinase—role in Duchenne muscular dystrophy. J Cell Sci 121:2246–2255. doi:10.1242/jcs.032003

    Article  PubMed  CAS  Google Scholar 

  61. Goel M, Sinkins WG, Schilling WP (2002) Selective association of TRPC channel subunits in rat brain synaptosomes. J Biol Chem 277:48303–48310. doi:10.1074/jbc.M207882200

    Article  PubMed  CAS  Google Scholar 

  62. Golovina VA, Platoshyn O, Bailey CL, Wang J, Limsuwan A, Sweeney M, Rubin LJ, Yuan JX (2001) Upregulated TRP and enhanced capacitative Ca(2+) entry in human pulmonary artery myocytes during proliferation. Am J Physiol Heart Circ Physiol 280:H746–H755

    PubMed  CAS  Google Scholar 

  63. Gorin Y, Ricono JM, Kim NH, Bhandari B, Choudhury GG, Abboud HE (2003) Nox4 mediates angiotensin II-induced activation of Akt/protein kinase B in mesangial cells. Am J Physiol Renal Physiol 285:F219–F229. doi:10.1152/ajprenal.00414.2002

    Article  PubMed  CAS  Google Scholar 

  64. Graciano MF, Valle MM, Kowluru A, Curi R, Carpinelli AR (2011) Regulation of insulin secretion and reactive oxygen species production by free fatty acids in pancreatic islets. Islets 3:213–223

    Article  PubMed  Google Scholar 

  65. Graham S, Ding M, Ding Y, Sours-Brothers S, Luchowski R, Gryczynski Z, Yorio T, Ma H, Ma R (2010) Canonical transient receptor potential 6 (TRPC6), a redox-regulated cation channel. J Biol Chem 285:23466–23476. doi:10.1074/jbc.M109.093500

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  66. Green DE, Murphy TC, Kang BY, Kleinhenz JM, Szyndralewiez C, Page P, Sutliff RL, Hart CM (2012) The Nox4 inhibitor GKT137831 attenuates hypoxia-induced pulmonary vascular cell proliferation. Am J Respir Cell Mol Biol 47:718–726. doi:10.1165/rcmb.2011-0418OC

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  67. Grimminger F, Weissmann N, Spriestersbach R, Becker E, Rosseau S, Seeger W (1995) Effects of NADPH oxidase inhibitors on hypoxic vasoconstriction in buffer-perfused rabbit lungs. Am J Physiol 268:L747–L752

    PubMed  CAS  Google Scholar 

  68. Gupte SA, Wolin MS (2012) Relationships between vascular oxygen sensing mechanisms and hypertensive disease processes. Hypertension 60:269–275. doi:10.1161/HYPERTENSIONAHA.112.190702

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  69. Gupte RS, Rawat DK, Chettimada S, Cioffi DL, Wolin MS, Gerthoffer WT, McMurtry IF, Gupte SA (2010) Activation of glucose-6-phosphate dehydrogenase promotes acute hypoxic pulmonary artery contraction. J Biol Chem 285:19561–19571. doi:10.1074/jbc.M109.092916

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  70. Han W, Li H, Villar VA, Pascua AM, Dajani MI, Wang X, Natarajan A, Quinn MT, Felder RA, Jose PA, Yu P (2008) Lipid rafts keep NADPH oxidase in the inactive state in human renal proximal tubule cells. Hypertension 51:481–487. doi:10.1161/HYPERTENSIONAHA.107.103275

    Article  PubMed  CAS  Google Scholar 

  71. Hara Y, Wakamori M, Ishii M, Maeno E, Nishida M, Yoshida T, Yamada H, Shimizu S, Mori E, Kudoh J, Shimizu N, Kurose H, Okada Y, Imoto K, Mori Y (2002) LTRPC2 Ca2+-permeable channel activated by changes in redox status confers susceptibility to cell death. Mol Cell 9:163–173

    Article  PubMed  CAS  Google Scholar 

  72. Hilenski LL, Clempus RE, Quinn MT, Lambeth JD, Griendling KK (2004) Distinct subcellular localizations of Nox1 and Nox4 in vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 24:677–683. doi:10.1161/01.ATV.0000112024.13727.2c

    Article  PubMed  CAS  Google Scholar 

  73. Hofmann T, Schaefer M, Schultz G, Gudermann T (2002) Subunit composition of mammalian transient receptor potential channels in living cells. Proc Natl Acad Sci U S A 99:7461–7466. doi:10.1073/pnas.102596199

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  74. Ikeda S, Yamaoka-Tojo M, Hilenski L, Patrushev NA, Anwar GM, Quinn MT, Ushio-Fukai M (2005) IQGAP1 regulates reactive oxygen species-dependent endothelial cell migration through interacting with Nox2. Arterioscler Thromb Vasc Biol 25:2295–2300. doi:10.1161/01.ATV.0000187472.55437.af

    Article  PubMed  CAS  Google Scholar 

  75. Ismail S, Sturrock A, Wu P, Cahill B, Norman K, Huecksteadt T, Sanders K, Kennedy T, Hoidal J (2009) NOX4 mediates hypoxia-induced proliferation of human pulmonary artery smooth muscle cells: the role of autocrine production of transforming growth factor-{beta}1 and insulin-like growth factor binding protein-3. Am J Physiol Lung Cell Mol Physiol 296:L489–L499. doi:10.1152/ajplung.90488.2008

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  76. Jiang F, Zhang Y, Dusting GJ (2011) NADPH oxidase-mediated redox signaling: roles in cellular stress response, stress tolerance, and tissue repair. Pharmacol Rev 63:218–242. doi:10.1124/pr.110.002980

    Article  PubMed  CAS  Google Scholar 

  77. Jiang Q, Fu X, Tian L, Chen Y, Yang K, Chen X, Zhang J, Lu W, Wang J (2014) NOX4 mediates BMP4-induced upregulation of TRPC1 and 6 protein expressions in distal pulmonary arterial smooth muscle cells. PLoS One 9:e107135. doi:10.1371/journal.pone.0107135

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  78. Jones RD, Thompson JS, Morice AH (2000) The NADPH oxidase inhibitors iodonium diphenyl and cadmium sulphate inhibit hypoxic pulmonary vasoconstriction in isolated rat pulmonary arteries. Physiol Res Acad Scientiarum Bohemoslov 49:587–596

    CAS  Google Scholar 

  79. Jonnala RR, Buccafusco JJ (2001) Inhibition of nerve growth factor signaling by peroxynitrite. J Neurosci Res 63:27–34

    Article  PubMed  CAS  Google Scholar 

  80. Kalinina N, Agrotis A, Tararak E, Antropova Y, Kanellakis P, Ilyinskaya O, Quinn MT, Smirnov V, Bobik A (2002) Cytochrome b558-dependent NAD(P)H oxidase-phox units in smooth muscle and macrophages of atherosclerotic lesions. Arterioscler Thromb Vasc Biol 22:2037–2043

    Article  PubMed  CAS  Google Scholar 

  81. Kamata H, Honda S, Maeda S, Chang L, Hirata H, Karin M (2005) Reactive oxygen species promote TNFalpha-induced death and sustained JNK activation by inhibiting MAP kinase phosphatases. Cell 120:649–661. doi:10.1016/j.cell.2004.12.041

    Article  PubMed  CAS  Google Scholar 

  82. Kawahara T, Jackson HM, Smith SM, Simpson PD, Lambeth JD (2011) Nox5 forms a functional oligomer mediated by self-association of its dehydrogenase domain. Biochemistry 50:2013–2025. doi:10.1021/bi1020088

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  83. Kim EY, Anderson M, Wilson C, Hagmann H, Benzing T, Dryer SE (2013) NOX2 interacts with podocyte TRPC6 channels and contributes to their activation by diacylglycerol: essential role of podocin in formation of this complex. Am J Physiol Cell Physiol 305:C960–C971. doi:10.1152/ajpcell.00191.2013

    Article  PubMed  CAS  Google Scholar 

  84. Kitajima N, Watanabe K, Morimoto S, Sato Y, Kiyonaka S, Hoshijima M, Ikeda Y, Nakaya M, Ide T, Mori Y, Kurose H, Nishida M (2011) TRPC3-mediated Ca2+ influx contributes to Rac1-mediated production of reactive oxygen species in MLP-deficient mouse hearts. Biochem Biophys Res Commun 409:108–113. doi:10.1016/j.bbrc.2011.04.124

    Article  PubMed  CAS  Google Scholar 

  85. Konior A, Schramm A, Czesnikiewicz-Guzik M, Guzik TJ (2014) NADPH oxidases in vascular pathology. Antioxid Redox Signal 20:2794–2814. doi:10.1089/ars.2013.5607

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  86. Kozai D, Ogawa N, Mori Y (2014) Redox regulation of transient receptor potential channels. Antioxid Redox Signal 21:971–986. doi:10.1089/ars.2013.5616

    Article  PubMed  CAS  Google Scholar 

  87. Laurindo FR, Araujo TL, Abrahao TB (2014) Nox NADPH oxidases and the endoplasmic reticulum. Antioxid Redox Signal 20:2755–2775. doi:10.1089/ars.2013.5605

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  88. Lee YM, Kim BJ, Chun YS, So I, Choi H, Kim MS, Park JW (2006) NOX4 as an oxygen sensor to regulate TASK-1 activity. Cell Signal 18:499–507. doi:10.1016/j.cellsig.2005.05.025

    Article  PubMed  CAS  Google Scholar 

  89. Lee H, Lee YJ, Choi H, Ko EH, Kim JW (2009) Reactive oxygen species facilitate adipocyte differentiation by accelerating mitotic clonal expansion. J Biol Chem 284:10601–10609. doi:10.1074/jbc.M808742200

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  90. Li S, Tabar SS, Malec V, Eul BG, Klepetko W, Weissmann N, Grimminger F, Seeger W, Rose F, Hanze J (2008) NOX4 regulates ROS levels under normoxic and hypoxic conditions, triggers proliferation, and inhibits apoptosis in pulmonary artery adventitial fibroblasts. Antioxid Redox Signal 10:1687–1698. doi:10.1089/ars.2008.2035

    Article  PubMed  CAS  Google Scholar 

  91. Li Q, Spencer NY, Oakley FD, Buettner GR, Engelhardt JF (2009) Endosomal Nox2 facilitates redox-dependent induction of NF-kappaB by TNF-alpha. Antioxid Redox Signal 11:1249–1263. doi:10.1089/ARS.2008.2407

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  92. Li X, Lu W, Fu X, Zhang Y, Yang K, Zhong N, Ran P, Wang J (2013) BMP4 increases canonical transient receptor potential protein expression by activating p38 MAPK and ERK1/2 signaling pathways in pulmonary arterial smooth muscle cells. Am J Respir Cell Mol Biol 49:212–220. doi:10.1165/rcmb.2012-0051OC

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  93. Liao B, Zheng YM, Yadav VR, Korde AS, Wang YX (2011) Hypoxia induces intracellular Ca2+ release by causing reactive oxygen species-mediated dissociation of FK506-binding protein 12.6 from ryanodine receptor 2 in pulmonary artery myocytes. Antioxid Redox Signal 14:37–47. doi:10.1089/ars.2009.3047

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  94. Lin M-J, Leung GPH, Zhang W-M, Yang X-R, Yip K-P, Tse C-M, Sham JSK (2004) 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. doi:10.1161/01.RES.0000138952.16382.ad

    Article  PubMed  CAS  Google Scholar 

  95. Lin MJ, Yang XR, Cao YN, Sham JS (2007) Hydrogen peroxide-induced Ca2+ mobilization in pulmonary arterial smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 292:L1598–L1608. doi:10.1152/ajplung.00323.2006

    Article  PubMed  CAS  Google Scholar 

  96. Liu X, Wang W, Singh BB, Lockwich T, Jadlowiec J, O'Connell B, Wellner R, Zhu MX, Ambudkar IS (2000) Trp1, a candidate protein for the store-operated Ca(2+) influx mechanism in salivary gland cells. J Biol Chem 275:3403–3411

    Article  PubMed  CAS  Google Scholar 

  97. Liu X, Bandyopadhyay BC, Singh BB, Groschner K, Ambudkar IS (2005) Molecular analysis of a store-operated and 2-acetyl-sn-glycerol-sensitive non-selective cation channel. Heteromeric assembly of TRPC1-TRPC3. J Biol Chem 280:21600–21606. doi:10.1074/jbc.C400492200

    Article  PubMed  CAS  Google Scholar 

  98. Liu JQ, Zelko IN, Erbynn EM, Sham JS, Folz RJ (2006) Hypoxic pulmonary hypertension: role of superoxide and NADPH oxidase (gp91phox). Am J Physiol Lung Cell Mol Physiol 290:L2–L10. doi:10.1152/ajplung.00135.2005

    Article  PubMed  CAS  Google Scholar 

  99. Lu W, Wang J, Shimoda LA, Sylvester JT (2008) 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. doi:10.1152/ajplung.00058.2008

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  100. Lu X, Murphy TC, Nanes MS, Hart CM (2010) PPAR{gamma} regulates hypoxia-induced Nox4 expression in human pulmonary artery smooth muscle cells through NF-{kappa}B. Am J Physiol Lung Cell Mol Physiol 299:L559–L566. doi:10.1152/ajplung.00090.2010

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  101. Lyle AN, Deshpande NN, Taniyama Y, Seidel-Rogol B, Pounkova L, Du P, Papaharalambus C, Lassegue B, Griendling KK (2009) Poldip2, a novel regulator of Nox4 and cytoskeletal integrity in vascular smooth muscle cells. Circ Res 105:249–259. doi:10.1161/CIRCRESAHA.109.193722

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  102. Majmundar AJ, Wong WJ, Simon MC (2010) Hypoxia-inducible factors and the response to hypoxic stress. Mol Cell 40:294–309. doi:10.1016/j.molcel.2010.09.022

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  103. Malczyk M, Veith C, Fuchs B, Hofmann K, Storch U, Schermuly RT, Witzenrath M, Ahlbrecht K, Fecher-Trost C, Flockerzi V, Ghofrani HA, Grimminger F, Seeger W, Gudermann T, Dietrich A, Weissmann N (2013) Classical transient receptor potential channel 1 in hypoxia-induced pulmonary hypertension. Am J Respir Crit Care Med 188:1451–1459. doi:10.1164/rccm.201307-1252OC

    Article  PubMed  CAS  Google Scholar 

  104. Marshall C, Mamary AJ, Verhoeven AJ, Marshall BE (1996) Pulmonary artery NADPH-oxidase is activated in hypoxic pulmonary vasoconstriction. Am J Respir Crit Care Med 15:633–644. doi:10.1165/ajrcmb.15.5.8918370

    CAS  Google Scholar 

  105. Matsushima S, Kuroda J, Ago T, Zhai P, Park JY, Xie LH, Tian B, Sadoshima J (2013) Increased oxidative stress in the nucleus caused by Nox4 mediates oxidation of HDAC4 and cardiac hypertrophy. Circ Res 112:651–663. doi:10.1161/CIRCRESAHA.112.279760

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  106. Matute JD, Arias AA, Dinauer MC, Patino PJ (2005) p40phox: the last NADPH oxidase subunit. Blood Cells Mol Dis 35:291–302. doi:10.1016/j.bcmd.2005.06.010

    Article  PubMed  CAS  Google Scholar 

  107. Meischl C, Krijnen PA, Sipkens JA, Cillessen SA, Munoz IG, Okroj M, Ramska M, Muller A, Visser CA, Musters RJ, Simonides WS, Hack CE, Roos D, Niessen HW (2006) Ischemia induces nuclear NOX2 expression in cardiomyocytes and subsequently activates apoptosis. Apoptosis : Int J Program Cell Death 11:913–921. doi:10.1007/s10495-006-6304-7

    Article  CAS  Google Scholar 

  108. Meredith D, Panchatcharam M, Miriyala S, Tsai YS, Morris AJ, Maeda N, Stouffer GA, Smyth SS (2009) Dominant-negative loss of PPARgamma function enhances smooth muscle cell proliferation, migration, and vascular remodeling. Arterioscler Thromb Vasc Biol 29:465–471. doi:10.1161/ATVBAHA.109.184234

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  109. Michelakis ED, Archer SL, Weir EK (1995) Acute hypoxic pulmonary vasoconstriction: a model of oxygen sensing. Physiol Res Acad Scientiarum Bohemoslov 44:361–367

    CAS  Google Scholar 

  110. Miller FJ Jr, Chu X, Stanic B, Tian X, Sharma RV, Davisson RL, Lamb FS (2010) A differential role for endocytosis in receptor-mediated activation of Nox1. Antioxid Redox Signal 12:583–593. doi:10.1089/ars.2009.2857

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  111. Mingone CJ, Gupte SA, Iesaki T, Wolin MS (2003) Hypoxia enhances a cGMP-independent nitric oxide relaxing mechanism in pulmonary arteries. Am J Physiol Lung Cell Mol Physiol 285:L296–L304. doi:10.1152/ajplung.00362.2002

    Article  PubMed  CAS  Google Scholar 

  112. Mittal M, Roth M, Konig P, Hofmann S, Dony E, Goyal P, Selbitz AC, Schermuly RT, Ghofrani HA, Kwapiszewska G, Kummer W, Klepetko W, Hoda MA, Fink L, Hanze J, Seeger W, Grimminger F, Schmidt HH, Weissmann N (2007) Hypoxia-dependent regulation of nonphagocytic NADPH oxidase subunit NOX4 in the pulmonary vasculature. Circ Res 101:258–267. doi:10.1161/CIRCRESAHA.107.148015

    Article  PubMed  CAS  Google Scholar 

  113. Mittal M, Gu XQ, Pak O, Pamenter ME, Haag D, Fuchs DB, Schermuly RT, Ghofrani HA, Brandes RP, Seeger W, Grimminger F, Haddad GG, Weissmann N (2012) Hypoxia induces Kv channel current inhibition by increased NADPH oxidase-derived reactive oxygen species. Free Radical Biol Med 52:1033–1042. doi:10.1016/j.freeradbiomed.2011.12.004

    Article  CAS  Google Scholar 

  114. Montezano AC, Touyz RM (2014) Reactive oxygen species, vascular Noxs, and hypertension: focus on translational and clinical research. Antioxid Redox Signal 20:164–182. doi:10.1089/ars.2013.5302

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  115. Moreno L, Moral-Sanz J, Morales-Cano D, Barreira B, Moreno E, Ferrarini A, Pandolfi R, Ruperez FJ, Cortijo J, Sanchez-Luna M, Villamor E, Perez-Vizcaino F, Cogolludo A (2014) Ceramide mediates acute oxygen sensing in vascular tissues. Antioxid Redox Signal 20:1–14. doi:10.1089/ars.2012.4752

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  116. Mottet D, Michel G, Renard P, Ninane N, Raes M, Michiels C (2003) Role of ERK and calcium in the hypoxia-induced activation of HIF-1. J Cell Physiol 194:30–44. doi:10.1002/jcp.10176

    Article  PubMed  CAS  Google Scholar 

  117. Moudgil R, Michelakis ED, Archer SL (2006) The role of K+ channels in determining pulmonary vascular tone, oxygen sensing, cell proliferation, and apoptosis: implications in hypoxic pulmonary vasoconstriction and pulmonary arterial hypertension. Microcirculation 13:615–632. doi:10.1080/10739680600930222

    Article  PubMed  CAS  Google Scholar 

  118. Murphy MP (2009) How mitochondria produce reactive oxygen species. Biochem J 417:1–13. doi:10.1042/BJ20081386

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  119. Nayernia Z, Jaquet V, Krause KH (2014) New insights on NOX enzymes in the central nervous system. Antioxid Redox Signal 20:2815–2837. doi:10.1089/ars.2013.5703

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  120. Ng LC, Gurney AM (2001) Store-operated channels mediate Ca(2+) influx and contraction in rat pulmonary artery. Circ Res 89:923–929

    Article  PubMed  CAS  Google Scholar 

  121. Nisbet RE, Bland JM, Kleinhenz DJ, Mitchell PO, Walp ER, Sutliff RL, Hart CM (2010) Rosiglitazone attenuates chronic hypoxia-induced pulmonary hypertension in a mouse model. Am J Respir Cell Mol Biol 42:482–490. doi:10.1165/rcmb.2008-0132OC

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  122. Oakley FD, Smith RL, Engelhardt JF (2009) Lipid rafts and caveolin-1 coordinate interleukin-1beta (IL-1beta)-dependent activation of NFkappaB by controlling endocytosis of Nox2 and IL-1beta receptor 1 from the plasma membrane. J Biol Chem 284:33255–33264. doi:10.1074/jbc.M109.042127

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  123. Ogura S, Shimosawa T, Mu S, Sonobe T, Kawakami-Mori F, Wang H, Uetake Y, Yoshida K, Yatomi Y, Shirai M, Fujita T (2013) Oxidative stress augments pulmonary hypertension in chronically hypoxic mice overexpressing the oxidized LDL receptor. Am J Physiol Heart Circ Physiol 305:H155–H162. doi:10.1152/ajpheart.00169.2012

    Article  PubMed  CAS  Google Scholar 

  124. Olschewski A, Weir EK (2015) Redox regulation of ion channels in the pulmonary circulation. Antioxid Redox Signal 22:465–485. doi:10.1089/ars.2014.5899

    Article  PubMed  CAS  Google Scholar 

  125. Ong HL, Cheng KT, Liu X, Bandyopadhyay BC, Paria BC, Soboloff J, Pani B, Gwack Y, Srikanth S, Singh BB, Gill DL, Gill D, Ambudkar IS (2007) Dynamic assembly of TRPC1-STIM1-Orai1 ternary complex is involved in store-operated calcium influx. Evidence for similarities in store-operated and calcium release-activated calcium channel components. J Biol Chem 282:9105–9116. doi:10.1074/jbc.M608942200

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  126. Ovechkin AV, Lominadze D, Sedoris KC, Robinson TW, Tyagi SC, Roberts AM (2007) Lung ischemia-reperfusion injury: implications of oxidative stress and platelet-arteriolar wall interactions. Arch Physiol Biochem 113:1–12. doi:10.1080/13813450601118976

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  127. Pak O, Aldashev A, Welsh D, Peacock A (2007) The effects of hypoxia on the cells of the pulmonary vasculature. Eur Res J Off J Eur Soc Clin Res Physiol 30:364–372. doi:10.1183/09031936.00128706

    CAS  Google Scholar 

  128. Pak O, Sommer N, Hoeres T, Bakr A, Waisbrod S, Sydykov A, Haag D, Esfandiary A, Kojonazarov B, Veit F, Fuchs B, Weisel FC, Hecker M, Schermuly RT, Grimminger F, Ghofrani HA, Seeger W, Weissmann N (2013) Mitochondrial hyperpolarization in pulmonary vascular remodeling. Mitochondrial uncoupling protein deficiency as disease model. Am J Respir Cell Mol Biol 49:358–367. doi:10.1165/rcmb.2012-0361OC

    Article  PubMed  CAS  Google Scholar 

  129. Panday A, Sahoo MK, Osorio D, Batra S (2015) NADPH oxidases: an overview from structure to innate immunity-associated pathologies. Cell Mol Immunol 12:5–23. doi:10.1038/cmi.2014.89

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  130. Pandey D, Patel A, Patel V, Chen F, Qian J, Wang Y, Barman SA, Venema RC, Stepp DW, Rudic RD, Fulton DJ (2012) Expression and functional significance of NADPH oxidase 5 (Nox5) and its splice variants in human blood vessels. Am J Physiol Heart Circ Physiol 302:H1919–H1928. doi:10.1152/ajpheart.00910.2011

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  131. Pani B, Ong HL, Brazer S-CW, Liu X, Rauser K, Singh BB, Ambudkar IS (2009) Activation of TRPC1 by STIM1 in ER-PM microdomains involves release of the channel from its scaffold caveolin-1. Proc Natl Acad Sci U S A 106:20087–20092. doi:10.1073/pnas.0905002106

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  132. Pani B, Liu X, Bollimuntha S, Cheng KT, Niesman IR, Zheng C, Achen VR, Patel HH, Ambudkar IS, Singh BB (2013) Impairment of TRPC1-STIM1 channel assembly and AQP5 translocation compromise agonist-stimulated fluid secretion in mice lacking caveolin1. J Cell Sci 126:667–675. doi:10.1242/jcs.118943

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  133. Peacock AJ, Scott P, Plevin R, Wadsworth R, Welsh D (1998) Hypoxia enhances proliferation and generation of IP3 in pulmonary artery fibroblasts but not in those from the mesenteric circulation. Chest 114:24S

    Article  PubMed  CAS  Google Scholar 

  134. Pedersen SF, Owsianik G, Nilius B (2005) TRP channels: an overview. Cell Calcium 38:233–252. doi:10.1016/j.ceca.2005.06.028

    Article  PubMed  CAS  Google Scholar 

  135. Peters SC, Piper HM (2007) Reoxygenation-induced Ca2+ rise is mediated via Ca2+ influx and Ca2+ release from the endoplasmic reticulum in cardiac endothelial cells. Cardiovasc Res 73:164–171. doi:10.1016/j.cardiores.2006.09.015

    Article  PubMed  CAS  Google Scholar 

  136. Raad H, Paclet MH, Boussetta T, Kroviarski Y, Morel F, Quinn MT, Gougerot-Pocidalo MA, Dang PM, El-Benna J (2009) Regulation of the phagocyte NADPH oxidase activity: phosphorylation of gp91phox/NOX2 by protein kinase C enhances its diaphorase activity and binding to Rac2, p67phox, and p47phox. FASEB J Off Pub Fed Am Soc Exp Biol 23:1011–1022. doi:10.1096/fj.08-114553

    CAS  Google Scholar 

  137. Rada B, Leto TL (2008) Oxidative innate immune defenses by Nox/Duox family NADPH oxidases. Contrib Microbiol 15:164–187. doi:10.1159/000136357

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  138. Ratz JD, McGuire JJ, Anderson DJ, Bennett BM (2000) Effects of the flavoprotein inhibitor, diphenyleneiodonium sulfate, on ex vivo organic nitrate tolerance in the rat. J Pharmacol Exp Ther 293:569–577

    PubMed  CAS  Google Scholar 

  139. Reading SA, Earley S, Waldron BJ, Welsh DG, Brayden JE (2005) TRPC3 mediates pyrimidine receptor-induced depolarization of cerebral arteries. Am J Physiol Heart Circ Physiol 288:H2055–H2061. doi:10.1152/ajpheart.00861.2004

    Article  PubMed  CAS  Google Scholar 

  140. Remillard CV, Yuan JX-J (2006) Transient receptor potential channels and caveolin-1: good friends in tight spaces. Mol Pharmacol 70:1151–1154. doi:10.1124/mol.106.029280

    Article  PubMed  CAS  Google Scholar 

  141. Robertson TP, Hague D, Aaronson PI, Ward JP (2000) Voltage-independent calcium entry in hypoxic pulmonary vasoconstriction of intrapulmonary arteries of the rat. J Physiol 525(Pt 3):669–680

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  142. Rodman DM, Reese K, Harral J, Fouty B, Wu S, West J, Hoedt-Miller M, Tada Y, Li K-X, Cool C, Fagan K, Cribbs L (2005) Low-voltage-activated (T-type) calcium channels control proliferation of human pulmonary artery myocytes. Circ Res 96:864–872. doi:10.1161/01.RES.0000163066.07472.ff

    Article  PubMed  CAS  Google Scholar 

  143. Roedding AS, Gao AF, Au-Yeung W, Scarcelli T, Li PP, Warsh JJ (2012) Effect of oxidative stress on TRPM2 and TRPC3 channels in B lymphoblast cells in bipolar disorder. Bipolar Disord 14:151–161. doi:10.1111/j.1399-5618.2012.01003.x

    Article  PubMed  CAS  Google Scholar 

  144. Roedding AS, Tong SY, Au-Yeung W, Li PP, Warsh JJ (2013) Chronic oxidative stress modulates TRPC3 and TRPM2 channel expression and function in rat primary cortical neurons: relevance to the pathophysiology of bipolar disorder. Brain Res 1517:16–27. doi:10.1016/j.brainres.2013.04.025

    Article  PubMed  CAS  Google Scholar 

  145. Savai R, Al-Tamari HM, Sedding D, Kojonazarov B, Muecke C, Teske R, Capecchi MR, Weissmann N, Grimminger F, Seeger W, Schermuly RT, Pullamsetti SS (2014) Pro-proliferative and inflammatory signaling converge on FoxO1 transcription factor in pulmonary hypertension. Nat Med 20:1289–1300. doi:10.1038/nm.3695

    Article  PubMed  CAS  Google Scholar 

  146. Schieber M, Chandel NS (2014) ROS function in redox signaling and oxidative stress. Curr Biol CB 24:R453–R462. doi:10.1016/j.cub.2014.03.034

    Article  PubMed  CAS  Google Scholar 

  147. Schindl R, Fritsch R, Jardin I, Frischauf I, Kahr H, Muik M, Riedl MC, Groschner K, Romanin C (2012) Canonical transient receptor potential (TRPC) 1 acts as a negative regulator for vanilloid TRPV6-mediated Ca2+ influx. J Biol Chem 287:35612–35620. doi:10.1074/jbc.M112.400952

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  148. Schroder K (2014) NADPH oxidases in redox regulation of cell adhesion and migration. Antioxid Redox Signal 20:2043–2058. doi:10.1089/ars.2013.5633

    Article  PubMed  CAS  Google Scholar 

  149. Schroder K, Kohnen A, Aicher A, Liehn EA, Buchse T, Stein S, Weber C, Dimmeler S, Brandes RP (2009) NADPH oxidase Nox2 is required for hypoxia-induced mobilization of endothelial progenitor cells. Circ Res 105:537–544. doi:10.1161/CIRCRESAHA.109.205138

    Article  PubMed  CAS  Google Scholar 

  150. Schroder K, Zhang M, Benkhoff S, Mieth A, Pliquett R, Kosowski J, Kruse C, Luedike P, Michaelis UR, Weissmann N, Dimmeler S, Shah AM, Brandes RP (2012) Nox4 is a protective reactive oxygen species generating vascular NADPH oxidase. Circ Res 110:1217–1225. doi:10.1161/CIRCRESAHA.112.267054

    Article  PubMed  CAS  Google Scholar 

  151. Schulz R, Murzabekova G, Egemnazarov B, Kraut S, Eisele HJ, Dumitrascu R, Heitmann J, Seimetz M, Witzenrath M, Ghofrani HA, Schermuly RT, Grimminger F, Seeger W, Weissmann N (2014) Arterial hypertension in a murine model of sleep apnea: role of NADPH oxidase 2. J Hypertens 32:300–305. doi:10.1097/HJH.0000000000000016

    Article  PubMed  CAS  Google Scholar 

  152. Schumacker PT (2011) Lung cell hypoxia: role of mitochondrial reactive oxygen species signaling in triggering responses. Proc Am Thorac Soc 8:477–484. doi:10.1513/pats.201103-032MW

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  153. Seshiah PN, Weber DS, Rocic P, Valppu L, Taniyama Y, Griendling KK (2002) Angiotensin II stimulation of NAD(P)H oxidase activity: upstream mediators. Circ Res 91:406–413

    Article  PubMed  CAS  Google Scholar 

  154. Shimoda LA, Wang J, Sylvester JT (2006) Ca2+ channels and chronic hypoxia. Microcirculation (New York NY 1994) 13:657–670. doi:10.1080/10739680600930305

    Article  CAS  Google Scholar 

  155. Shinohara M, Shang WH, Kubodera M, Harada S, Mitsushita J, Kato M, Miyazaki H, Sumimoto H, Kamata T (2007) Nox1 redox signaling mediates oncogenic Ras-induced disruption of stress fibers and focal adhesions by down-regulating Rho. J Biol Chem 282:17640–17648. doi:10.1074/jbc.M609450200

    Article  PubMed  CAS  Google Scholar 

  156. Simon HU, Haj-Yehia A, Levi-Schaffer F (2000) Role of reactive oxygen species (ROS) in apoptosis induction. Apoptosis Int J Program Cell Death 5:415–418

    Article  CAS  Google Scholar 

  157. Sommer N, Dietrich A, Schermuly RT, Ghofrani HA, Gudermann T, Schulz R, Seeger W, Grimminger F, Weissmann N (2008) Regulation of hypoxic pulmonary vasoconstriction: basic mechanisms. Eur Res J Off J Eur Soc Clin Res Physiol 32:1639–1651. doi:10.1183/09031936.00013908

    CAS  Google Scholar 

  158. Sommer N, Pak O, Schorner S, Derfuss T, Krug A, Gnaiger E, Ghofrani HA, Schermuly RT, Huckstorf C, Seeger W, Grimminger F, Weissmann N (2010) Mitochondrial cytochrome redox states and respiration in acute pulmonary oxygen sensing. Eur Res J Off J Eur Soc Clin Res Physiol 36:1056–1066. doi:10.1183/09031936.00013809

    CAS  Google Scholar 

  159. Stenmark KR, Fagan KA, Frid MG (2006) Hypoxia-induced pulmonary vascular remodeling: cellular and molecular mechanisms. Circ Res 99:675–691. doi:10.1161/01.RES.0000243584.45145.3f

    Article  PubMed  CAS  Google Scholar 

  160. Storch U, Forst A-L, Philipp M, Gudermann T, Mederos y Schnitzler M (2012) Transient receptor potential channel 1 (TRPC1) reduces calcium permeability in heteromeric channel complexes. J Biol Chem 287:3530–3540. doi:10.1074/jbc.M111.283218

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  161. Strübing C, Krapivinsky G, Krapivinsky L, Clapham DE (2001) TRPC1 and TRPC5 form a novel cation channel in mammalian brain. Neuron 29:645–655

    Article  PubMed  Google Scholar 

  162. Sturrock A, Cahill B, Norman K, Huecksteadt TP, Hill K, Sanders K, Karwande SV, Stringham JC, Bull DA, Gleich M, Kennedy TP, Hoidal JR (2006) Transforming growth factor-beta1 induces Nox4 NAD(P)H oxidase and reactive oxygen species-dependent proliferation in human pulmonary artery smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 290:L661–L673. doi:10.1152/ajplung.00269.2005

    Article  PubMed  CAS  Google Scholar 

  163. Sundivakkam PC, Kwiatek AM, Sharma TT, Minshall RD, Malik AB, Tiruppathi C (2009) Caveolin-1 scaffold domain interacts with TRPC1 and IP3R3 to regulate Ca2+ store release-induced Ca2+ entry in endothelial cells. Am J Physiol Cell Physiol 296:C403–C413. doi:10.1152/ajpcell.00470.2008

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  164. Sylvester JT, Shimoda LA, Aaronson PI, Ward JP (2012) Hypoxic pulmonary vasoconstriction. Physiol Rev 92:367–520. doi:10.1152/physrev.00041.2010

    Article  PubMed  CAS  Google Scholar 

  165. Tabeling C, Yu H, Wang L, Ranke H, Goldenberg NM, Zabini D, Noe E, Krauszman A, Gutbier B, Yin J, Schaefer M, Arenz C, Hocke AC, Suttorp N, Proia RL, Witzenrath M, Kuebler WM (2015) CFTR and sphingolipids mediate hypoxic pulmonary vasoconstriction. Proc Natl Acad Sci U S A 112:E1614–E1623. doi:10.1073/pnas.1421190112

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  166. Takac I, Schroder K, Zhang L, Lardy B, Anilkumar N, Lambeth JD, Shah AM, Morel F, Brandes RP (2011) The E-loop is involved in hydrogen peroxide formation by the NADPH oxidase Nox4. J Biol Chem 286:13304–13313. doi:10.1074/jbc.M110.192138

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  167. Takac I, Schroder K, Brandes RP (2012) The Nox family of NADPH oxidases: friend or foe of the vascular system? Curr Hypertens Rep 14:70–78. doi:10.1007/s11906-011-0238-3

    Article  PubMed  CAS  Google Scholar 

  168. Takahashi N, Mori Y (2011) TRP channels as sensors and signal integrators of redox status changes. Front Pharmacol 2:58. doi:10.3389/fphar.2011.00058

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  169. Takahashi N, Mizuno Y, Kozai D, Yamamoto S, Kiyonaka S, Shibata T, Uchida K, Mori Y (2008) Molecular characterization of TRPA1 channel activation by cysteine-reactive inflammatory mediators. Channels (Austin) 2:287–298

    Article  Google Scholar 

  170. Takahashi N, Kuwaki T, Kiyonaka S, Numata T, Kozai D, Mizuno Y, Yamamoto S, Naito S, Knevels E, Carmeliet P, Oga T, Kaneko S, Suga S, Nokami T, Yoshida J-I, Mori Y (2011) TRPA1 underlies a sensing mechanism for O2. Nat Chem Biol 7:701–711. doi:10.1038/nchembio.640

    Article  PubMed  CAS  Google Scholar 

  171. Tang C, To WK, Meng F, Wang Y, Gu Y (2010) A role for receptor-operated Ca2+ entry in human pulmonary artery smooth muscle cells in response to hypoxia. Physiol Res Acad Sci Bohemoslov 59:909–918

    CAS  Google Scholar 

  172. Thannickal VJ, Fanburg BL (2000) Reactive oxygen species in cell signaling. Am J Physiol Lung Cell Mol Physiol 279:L1005–L1028

    PubMed  CAS  Google Scholar 

  173. Thilo F, Lee M, Xia S, Zakrzewicz A, Tepel M (2014) High glucose modifies transient receptor potential canonical type 6 channels via increased oxidative stress and syndecan-4 in human podocytes. Biochem Biophys Res Commun 450:312–317. doi:10.1016/j.bbrc.2014.05.116

    Article  PubMed  CAS  Google Scholar 

  174. Thomas HM 3rd, Carson RC, Fried ED, Novitch RS (1991) Inhibition of hypoxic pulmonary vasoconstriction by diphenyleneiodonium. Biochem Pharmacol 42:R9–R12

    Article  PubMed  CAS  Google Scholar 

  175. Tiruppathi C, Freichel M, Vogel SM, Paria BC, Mehta D, Flockerzi V, Malik AB (2002) Impairment of store-operated Ca2+ entry in TRPC4(−/−) mice interferes with increase in lung microvascular permeability. Circ Res 91:70–76

    Article  PubMed  CAS  Google Scholar 

  176. Tiruppathi C, Ahmmed GU, Vogel SM, Malik AB (2006) Ca2+ signaling, TRP channels, and endothelial permeability. Microcirculation (New York NY 1994) 13:693–708. doi:10.1080/10739680600930347

    Article  CAS  Google Scholar 

  177. Touyz RM, Briones AM, Sedeek M, Burger D, Montezano AC (2011) NOX isoforms and reactive oxygen species in vascular health. Mol Interv 11:27–35. doi:10.1124/mi.11.1.5

    Article  PubMed  CAS  Google Scholar 

  178. Tsiokas L, Arnould T, Zhu C, Kim E, Walz G, Sukhatme VP (1999) Specific association of the gene product of PKD2 with the TRPC1 channel. Proc Natl Acad Sci U S A 96:3934–3939

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  179. Veit F, Pak O, Egemnazarov B, Roth M, Kosanovic D, Seimetz M, Sommer N, Ghofrani HA, Seeger W, Grimminger F, Brandes RP, Schermuly RT, Weissmann N (2013) Function of NADPH oxidase 1 in pulmonary arterial smooth muscle cells after monocrotaline-induced pulmonary vascular remodeling. Antioxid Redox Signal 19:2213–2231. doi:10.1089/ars.2012.4904

    Article  PubMed  CAS  Google Scholar 

  180. Veit F, Pak O, Brandes RP, Weissmann N (2015) Hypoxia-dependent reactive oxygen species signaling in the pulmonary circulation: focus on ion channels. Antioxid Redox Signal 22:537–552. doi:10.1089/ars.2014.6234

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  181. Viner RI, Williams TD, Schoneich C (1999) Peroxynitrite modification of protein thiols: oxidation, nitrosylation, and S-glutathiolation of functionally important cysteine residue(s) in the sarcoplasmic reticulum Ca-ATPase. Biochemistry 38:12408–12415

    Article  PubMed  CAS  Google Scholar 

  182. Von Euler US, Liljestrand G (1946) Observations on the pulmonary arterial blood pressure in the cat. Acta Physiol Scand 12:301–332

    Article  Google Scholar 

  183. Wan J, Yamamura A, Zimnicka AM, Voiriot G, Smith KA, Tang H, Ayon RJ, Choudhury MSR, Ko EA, Wang J, Wang C, Makino A, Yuan JX-J (2013) Chronic hypoxia selectively enhances L- and T-type voltage-dependent Ca2+ channel activity in pulmonary artery by upregulating Cav1.2 and Cav3.2. Am J Physiol Lung Cell Mol Physiol 305:L154–L164. doi:10.1152/ajplung.00313.2012

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  184. Wang J, Shimoda LA, Weigand L, Wang W, Sun D, Sylvester JT (2005) Acute hypoxia increases intracellular [Ca2+] in pulmonary arterial smooth muscle by enhancing capacitative Ca2+ entry. Am J Physiol Lung Cell Mol Physiol 288:L1059–L1069. doi:10.1152/ajplung.00448.2004

    Article  PubMed  CAS  Google Scholar 

  185. Wang J, Weigand L, Lu W, Sylvester JT, Semenza GL, Shimoda LA (2006) Hypoxia inducible factor 1 mediates hypoxia-induced TRPC expression and elevated intracellular Ca2+ in pulmonary arterial smooth muscle cells. Circ Res 98:1528–1537. doi:10.1161/01.RES.0000227551.68124.98

    Article  PubMed  CAS  Google Scholar 

  186. Wang Y, Deng X, Hewavitharana T, Soboloff J, Gill DL (2008) Stim, ORAI and TRPC channels in the control of calcium entry signals in smooth muscle. Clin Exp Pharmacol Physiol 35:1127–1133. doi:10.1111/j.1440-1681.2008.05018.x

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  187. Wang Y, Ding M, Chaudhari S, Ding Y, Yuan J, Stankowska D, He S, Krishnamoorthy R, Cunningham JT, Ma R (2013) Nuclear factor κB mediates suppression of canonical transient receptor potential 6 expression by reactive oxygen species and protein kinase C in kidney cells. J Biol Chem 288:12852–12865. doi:10.1074/jbc.M112.410357

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  188. Wang J, Fu X, Yang K, Jiang Q, Chen Y, Jia J, Duan X, Wang EW, He J, Ran P, Zhong N, Semenza GL, Lu W (2015) Hypoxia inducible factor-1-dependent up-regulation of BMP4 mediates hypoxia-induced increase of TRPC expression in PASMCs. Cardiovasc Res 107:108–118. doi:10.1093/cvr/cvv122

    Article  PubMed  Google Scholar 

  189. Waypa GB, Schumacker PT (2005) Hypoxic pulmonary vasoconstriction: redox events in oxygen sensing. J Appl Physiol Res Environ Exercise Physiol 98:404–414. doi:10.1152/japplphysiol.00722.2004

    CAS  Google Scholar 

  190. Waypa GB, Guzy R, Mungai PT, Mack MM, Marks JD, Roe MW, Schumacker PT (2006) Increases in mitochondrial reactive oxygen species trigger hypoxia-induced calcium responses in pulmonary artery smooth muscle cells. Circ Res 99:970–978. doi:10.1161/01.RES.0000247068.75808.3f

    Article  PubMed  CAS  Google Scholar 

  191. Waypa GB, Marks JD, Guzy R, Mungai PT, Schriewer J, Dokic D, Schumacker PT (2010) Hypoxia triggers subcellular compartmental redox signaling in vascular smooth muscle cells. Circ Res 106:526–535. doi:10.1161/CIRCRESAHA.109.206334

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  192. Waypa GB, Marks JD, Guzy RD, Mungai PT, Schriewer JM, Dokic D, Ball MK, Schumacker PT (2013) Superoxide generated at mitochondrial complex III triggers acute responses to hypoxia in the pulmonary circulation. Am J Respir Crit Care Med 187:424–432. doi:10.1164/rccm.201207-1294OC

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  193. Weaver M, Dunn NR, Hogan BL (2000) Bmp4 and Fgf10 play opposing roles during lung bud morphogenesis. Development 127:2695–2704

    PubMed  CAS  Google Scholar 

  194. Wedgwood S, Dettman RW, Black SM (2001) ET-1 stimulates pulmonary arterial smooth muscle cell proliferation via induction of reactive oxygen species. Am J Physiol Lung Cell Mol Physiol 281:L1058–L1067

    PubMed  CAS  Google Scholar 

  195. Weigand L, Foxson J, Wang J, Shimoda LA, Sylvester JT (2005) 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. doi:10.1152/ajplung.00044.2005

    Article  PubMed  CAS  Google Scholar 

  196. Weir EK, Archer SL (2010) The role of redox changes in oxygen sensing. Respir Physiol Neurobiol 174:182–191. doi:10.1016/j.resp.2010.08.015

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  197. Weir EK, Olschewski A (2006) Role of ion channels in acute and chronic responses of the pulmonary vasculature to hypoxia. Cardiovasc Res 71:630–641. doi:10.1016/j.cardiores.2006.04.014

    Article  PubMed  CAS  Google Scholar 

  198. Weissmann N, Tadic A, Hanze J, Rose F, Winterhalder S, Nollen M, Schermuly RT, Ghofrani HA, Seeger W, Grimminger F (2000) Hypoxic vasoconstriction in intact lungs: a role for NADPH oxidase-derived H(2)O(2)? Am J Physiol Lung Cell Mol Physiol 279:L683–L690

    PubMed  CAS  Google Scholar 

  199. Weissmann N, Akkayagil E, Quanz K, Schermuly RT, Ghofrani HA, Fink L, Hanze J, Rose F, Seeger W, Grimminger F (2004) Basic features of hypoxic pulmonary vasoconstriction in mice. Respir Physiol Neurobiol 139:191–202. doi:10.1016/j.resp.2003.10.003

    Article  PubMed  Google Scholar 

  200. Weissmann N, Dietrich A, Fuchs B, Kalwa H, Ay M, Dumitrascu R, Olschewski A, Storch U, Mederos y Schnitzler M, Ghofrani HA, Schermuly RT, Pinkenburg O, Seeger W, Grimminger F, Gudermann T (2006) Classical transient receptor potential channel 6 (TRPC6) is essential for hypoxic pulmonary vasoconstriction and alveolar gas exchange. Proc Natl Acad Sci U S A 103:19093–19098. doi:10.1073/pnas.0606728103

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  201. Weissmann N, Sommer N, Schermuly RT, Ghofrani HA, Seeger W, Grimminger F (2006) Oxygen sensors in hypoxic pulmonary vasoconstriction. Cardiovasc Res 71:620–629. doi:10.1016/j.cardiores.2006.04.009

    Article  PubMed  CAS  Google Scholar 

  202. Weissmann N, Zeller S, Schafer RU, Turowski C, Ay M, Quanz K, Ghofrani HA, Schermuly RT, Fink L, Seeger W, Grimminger F (2006) Impact of mitochondria and NADPH oxidases on acute and sustained hypoxic pulmonary vasoconstriction. Am J Respir Cell Mol Biol 34:505–513. doi:10.1165/rcmb.2005-0337OC

    Article  PubMed  CAS  Google Scholar 

  203. Weissmann N, Sydykov A, Kalwa H, Storch U, Fuchs B, Mederos y Schnitzler M, Brandes RP, Grimminger F, Meissner M, Freichel M, Offermanns S, Veit F, Pak O, Krause KH, Schermuly RT, Brewer AC, Schmidt HH, Seeger W, Shah AM, Gudermann T, Ghofrani HA, Dietrich A (2012) Activation of TRPC6 channels is essential for lung ischaemia-reperfusion induced oedema in mice. Nat Commun 3:649. doi:10.1038/ncomms1660

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  204. Welsh DJ, Scott P, Plevin R, Wadsworth R, Peacock AJ (1998) Hypoxia enhances cellular proliferation and inositol 1,4,5-triphosphate generation in fibroblasts from bovine pulmonary artery but not from mesenteric artery. Am J Respir Crit Care Med 158:1757–1762. doi:10.1164/ajrccm.158.6.9706054

    Article  PubMed  CAS  Google Scholar 

  205. Wheaton WW, Chandel NS (2011) Hypoxia. 2. Hypoxia regulates cellular metabolism. Am J Physiol Cell Physiol 300:C385–C393. doi:10.1152/ajpcell.00485.2010

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  206. Wolin MS, Ahmad M, Gupte SA (2005) Oxidant and redox signaling in vascular oxygen sensing mechanisms: basic concepts, current controversies, and potential importance of cytosolic NADPH. Am J Physiol Lung Cell Mol Physiol 289:L159–L173. doi:10.1152/ajplung.00060.2005

    Article  PubMed  CAS  Google Scholar 

  207. Wong CM, Bansal G, Pavlickova L, Marcocci L, Suzuki YJ (2012) Reactive oxygen species and antioxidants in pulmonary hypertension. Antioxid Redox Signal. doi:10.1089/ars.2012.4568

    PubMed Central  Google Scholar 

  208. Wright DC, Geiger PC, Han DH, Jones TE, Holloszy JO (2007) Calcium induces increases in peroxisome proliferator-activated receptor gamma coactivator-1alpha and mitochondrial biogenesis by a pathway leading to p38 mitogen-activated protein kinase activation. J Biol Chem 282:18793–18799. doi:10.1074/jbc.M611252200

    Article  PubMed  CAS  Google Scholar 

  209. Xia Y, Zweier JL (1997) Superoxide and peroxynitrite generation from inducible nitric oxide synthase in macrophages. Proc Natl Acad Sci U S A 94:6954–6958

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  210. Xia Y, Yang X-R, Fu Z, Paudel O, Abramowitz J, Birnbaumer L, Sham JSK (2014) Classical transient receptor potential 1 and 6 contribute to hypoxic pulmonary hypertension through differential regulation of pulmonary vascular functions. Hypertension 63:173–180. doi:10.1161/HYPERTENSIONAHA.113.01902

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  211. Xu S-Z, Sukumar P, Zeng F, Li J, Jairaman A, English A, Naylor J, Ciurtin C, Majeed Y, Milligan CJ, Bahnasi YM, Al-Shawaf E, Porter KE, Jiang L-H, Emery P, Sivaprasadarao A, Beech DJ (2008) TRPC channel activation by extracellular thioredoxin. Nature 451:69–72. doi:10.1038/nature06414

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  212. Yoshida T, Inoue R, Morii T, Takahashi N, Yamamoto S, Hara Y, Tominaga M, Shimizu S, Sato Y, Mori Y (2006) Nitric oxide activates TRP channels by cysteine S-nitrosylation. Nat Chem Biol 2:596–607. doi:10.1038/nchembio821

    Article  PubMed  CAS  Google Scholar 

  213. Yu L, Hales CA (2011) Hypoxia does neither stimulate pulmonary artery endothelial cell proliferation in mice and rats with pulmonary hypertension and vascular remodeling nor in human pulmonary artery endothelial cells. J Vasc Res 48:465–475. doi:10.1159/000327005

    Article  PubMed  PubMed Central  Google Scholar 

  214. Yu Y, Fantozzi I, Remillard CV, Landsberg JW, Kunichika N, Platoshyn O, Tigno DD, Thistlethwaite PA, Rubin LJ, Yuan JX-J (2004) Enhanced expression of transient receptor potential channels in idiopathic pulmonary arterial hypertension. Proc Natl Acad Sci U S A 101:13861–13866. doi:10.1073/pnas.0405908101

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  215. Yu Y, Keller SH, Remillard CV, Safrina O, Nicholson A, Zhang SL, Jiang W, Vangala N, Landsberg JW, Wang JY, Thistlethwaite PA, Channick RN, Robbins IM, Loyd JE, Ghofrani HA, Grimminger F, Schermuly RT, Cahalan MD, Rubin LJ, Yuan JX (2009) A functional single-nucleotide polymorphism in the TRPC6 gene promoter associated with idiopathic pulmonary arterial hypertension. Circulation 119:2313–2322. doi:10.1161/CIRCULATIONAHA.108.782458

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  216. Zhang J, Hu H, Palma NL, Harrison JK, Mubarak KK, Carrie RD, Alnuaimat H, Shen X, Luo D, Patel JM (2012) Hypoxia-induced endothelial CX3CL1 triggers lung smooth muscle cell phenotypic switching and proliferative expansion. Am J Physiol Lung Cell Mol Physiol 303:L912–L922. doi:10.1152/ajplung.00014.2012

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  217. Zhang J, Zhou J, Cai L, Lu Y, Wang T, Zhu L, Hu Q (2012) Extracellular calcium-sensing receptor is critical in hypoxic pulmonary vasoconstriction. Antioxid Redox Signal 17:471–484. doi:10.1089/ars.2011.4168

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Universities of Giessen and Marburg Lung Center (UGMLC), Excellence Cluster Cardiopulmonary System (ECCPS), Member of the German Center for Lung Research (DZL), Aulweg 130, 35392, Giessen, Germany

    Monika Malczyk, Christine Veith, Ralph T. Schermuly, Natascha Sommer, Norbert Weissmann & Oleg Pak

  2. Walther-Straub-Institute for Pharmacology and Toxicology, Ludwig-Maximilians University Munich, Member of the German Center for Lung Research (DZL), Munich, Germany

    Thomas Gudermann & Alexander Dietrich

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  1. Monika Malczyk
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  2. Christine Veith
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  3. Ralph T. Schermuly
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  4. Thomas Gudermann
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Correspondence to Norbert Weissmann.

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Malczyk, M., Veith, C., Schermuly, R.T. et al. NADPH oxidases—do they play a role in TRPC regulation under hypoxia?. Pflugers Arch - Eur J Physiol 468, 23–41 (2016). https://doi.org/10.1007/s00424-015-1731-3

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