NOX4 mediates hypoxia-induced proliferation of human pulmonary artery smooth muscle cells: the role of autocrine production of transforming growth factor-β1 and insulin-like growth factor binding protein-3
Open accessAbstract
Persistent hypoxia can cause pulmonary arterial hypertension that may be associated with significant remodeling of the pulmonary arteries, including smooth muscle cell proliferation and hypertrophy. We previously demonstrated that the NADPH oxidase homolog NOX4 mediates human pulmonary artery smooth muscle cell (HPASMC) proliferation by transforming growth factor-β1 (TGF-β1). We now show that hypoxia increases HPASMC proliferation in vitro, accompanied by increased reactive oxygen species generation and NOX4 gene expression, and is inhibited by antioxidants, the flavoenzyme inhibitor diphenyleneiodonium (DPI), and NOX4 gene silencing. HPASMC proliferation and NOX4 expression are also observed when media from hypoxic HPASMC are added to HPASMC grown in normoxic conditions, suggesting autocrine stimulation. TGF-β1 and insulin-like growth factor binding protein-3 (IGFBP-3) are both increased in the media of hypoxic HPASMC, and increased IGFBP-3 gene expression is noted in hypoxic HPASMC. Treatment with anti-TGF-β1 antibody attenuates NOX4 and IGFBP-3 gene expression, accumulation of IGFBP-3 protein in media, and proliferation. Inhibition of IGFBP-3 expression with small interfering RNA (siRNA) decreases NOX4 gene expression and hypoxic proliferation. Conversely, NOX4 silencing does not decrease hypoxic IGFBP-3 gene expression or secreted protein. Smad inhibition does not but the phosphatidylinositol 3-kinase (PI3K) signaling pathway inhibitor LY-294002 does inhibit NOX4 and IGFBP-3 gene expression, IGFBP-3 secretion, and cellular proliferation resulting from hypoxia. Immunoblots from hypoxic HPASMC reveal increased TGF-β1-mediated phosphorylation of the serine/threonine kinase (Akt), consistent with hypoxia-induced activation of PI3K/Akt signaling pathways to promote proliferation. We conclude that hypoxic HPASMC produce TGF-β1 that acts in an autocrine fashion to induce IGFBP-3 through PI3K/Akt. IGFBP-3 increases NOX4 gene expression, resulting in HPASMC proliferation. These observations add to our understanding hypoxic pulmonary vascular remodeling.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Other regulators of NOX4 include TNF-α, hypoxia, and PDGF.
“Other regulators include TNF-α (70, 681, 884, 1048), hypoxia (455), and PDGF (487).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [455]
Cites
Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2−ΔΔCT Method
Livak, K. J., & Schmittgen, T. D. (2001) · Methods · doi:10.1006/meth.2001.1262 · Cited by 180,860 · see citing works
The NOX Family of ROS-Generating NADPH Oxidases: Physiology and Pathophysiology
Bedard, K., & Krause, K.-H. (2007) · Physiological Reviews · doi:10.1152/physrev.00044.2005 · Cited by 6,989 · see citing works
AKT/PKB signaling: navigating downstream
Manning, B. D., & Cantley, L. C. (2007) · Cell · doi:10.1016/j.cell.2007.06.009 · Cited by 6,115 · see citing works
Jaakkola, P., Mole, D. R., Tian, Y.-M., Wilson, M. I., Gielbert, J., Gaskell, S. J., Kriegsheim, A. V., Hebestreit, H. F., Mukherji, M., Schofield, C. J., et al. (2001) · Science · doi:10.1126/science.1059796 · Cited by 5,535 · see citing works
Smad-dependent and Smad-independent pathways in TGF-β family signalling
Derynck, R., & Zhang, Y. E. (2003) · Nature · doi:10.1038/nature02006 · Cited by 5,370 · see citing works
Ivan, M., Kondo, K., Yang, H., Kim, W., Valiando, J., Ohh, M., Salic, A., Asara, J. M., Lane, W. S., & Kaelin Jr., W. G. (2001) · Science · doi:10.1126/science.1059817 · Cited by 4,735 · see citing works
Epstein, A. C. R., Gleadle, J. M., McNeill, L. A., Hewitson, K. S., O'Rourke, J., Mole, D. R., Mukherji, M., Metzen, E., Wilson, M. I., Dhanda, A., et al. (2001) · Cell · doi:10.1016/s0092-8674(01)00507-4 · Cited by 3,333 · see citing works
NOX enzymes and the biology of reactive oxygen
Lambeth, J. D. (2004) · Nature Reviews Immunology · doi:10.1038/nri1312 · Cited by 3,125 · see citing works
Cellular Actions of the Insulin-Like Growth Factor Binding Proteins
Firth, S. M., & Baxter, R. C. (2002) · Endocrine Reviews · doi:10.1210/er.2001-0033 · Cited by 1,754 · see citing works
Cellular and molecular pathobiology of pulmonary arterial hypertension
Humbert, M. J. C., Morrell, N. W., Archer, S. L., Stenmark, K. R., MacLean, M. R., Lang, I. M., Christman, B. W., Weir, Ε. K., Eickelberg, O., Voelkel, N. F., et al. (2004) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2004.02.029 · Cited by 1,574 · see citing works
Cell transformation by the superoxide-generating oxidase Mox1
Suh, Y.-A., Arnold, R. S., Lassegue, B., Shi, J., Xu, X., Sorescu, D., Chung, A. B., Griendling, K. K., & Lambeth, J. D. (1999) · Nature · doi:10.1038/43459 · Cited by 1,480 · see citing works
Pulmonary Arterial Hypertension
Farber, H. W., & Loscalzo, J. (2004) · New England Journal of Medicine · doi:10.1056/nejmra035488 · Cited by 1,460 · see citing works
Berra, E., Benizri, E., Ginouvès, A., Volmat, V., Roux, D., & Pouysségur, J. (2003) · The EMBO Journal · doi:10.1093/emboj/cdg392 · Cited by 1,348 · see citing works
Hypoxia-Induced Pulmonary Vascular Remodeling
Stenmark, K. R., Fagan, K. A., & Frid, M. G. (2006) · Circulation Research · doi:10.1161/01.res.0000243584.45145.3f · Cited by 1,001 · see citing works
Bakin, A. V., Tomlinson, A. K., Bhowmick, N. A., Moses, H. L., & Arteaga, C. L. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m005912200 · Cited by 987 · see citing works
Superoxide Production and Expression of Nox Family Proteins in Human Atherosclerosis
Sorescu, D., Weiss, D., Lassègue, B., Clempus, R. E., Szöcs, K., Sorescu, G. P., Valppu, L., Quinn, M. T., Lambeth, J. D., Vega, J. D., et al. (2002) · Circulation · doi:10.1161/01.cir.0000012917.74432.66 · Cited by 847 · see citing works
Identification of Renox, an NAD(P)H oxidase in kidney
Geiszt, M., Kopp, J. B., Várnai, P., & Leto, T. L. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.130135897 · Cited by 840 · see citing works
Lassègue, B., Sorescu, D., Szöcs, K., Yin, Q., Akers, M., Zhang, Y., Grant, S. L., Lambeth, J. D., & Griendling, K. K. (2001) · Circulation Research · doi:10.1161/hh0901.090299 · Cited by 839 · see citing works
Homologs of gp91 phox : cloning and tissue expression of Nox3, Nox4, and Nox5
Cheng, G., Cao, Z., Xu, X., Meir, E. G. V., & Lambeth, J. D. (2001) · Gene · doi:10.1016/s0378-1119(01)00449-8 · Cited by 820 · see citing works
Trembath, R. C., Thomson, J. R., Machado, R. D., Morgan, N. V., Atkinson, C., Winship, I., Simonneau, G., Galiè, N., Loyd, J. E., Humbert, M. J. C., et al. (2001) · New England Journal of Medicine · doi:10.1056/nejm200108023450503 · Cited by 725 · see citing works
Yu, A. Y., Shimoda, L. A., Iyer, N. V., Huso, D. L., Sun, X., McWilliams, R. M., Beaty, T. H., Sham, J. S. K., Wiener, C. M., Sylvester, J. T., et al. (1999) · Journal of Clinical Investigation · doi:10.1172/jci5912 · Cited by 645 · see citing works
NOX4 activity is determined by mRNA levels and reveals a unique pattern of ROS generation
Serrander, L., Cartier, L., Bedard, K., Banfi, B., Lardy, B., Plastre, O., Sienkiewicz, A., Fórró, L., Schlegel, W., & Krause, K.-H. (2007) · Biochemical Journal · doi:10.1042/bj20061903 · Cited by 627 · see citing works
Touyz, R. M., Chen, X., Tabet, F., Yao, G., He, G., Quinn, M. T., Pagano, P. J., & Schiffrin, E. L. (2002) · Circulation Research · doi:10.1161/01.res.0000020404.01971.2f · Cited by 590 · see citing works
A Novel Superoxide-producing NAD(P)H Oxidase in Kidney
Shiose, A., Kuroda, J., Tsuruya, K., Hirai, M., Hirakata, H., Naito, S., Hattori, M., Sakaki, Y., & Sumimoto, H. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m007597200 · Cited by 517 · see citing works
Morrell, N. W., Yang, X., Upton, P. D., et al. (2001) · Circulation · doi:10.1161/hc3201.094152 · Cited by 459 · see citing works
IGF-binding proteins are multifunctional and act via IGF-dependent and -independent mechanisms
Mohan, S., & Baylink, D. J. (2002) · Journal of Endocrinology · doi:10.1677/joe.0.1750019 · Cited by 444 · see citing works
Upregulation of Nox-Based NAD(P)H Oxidases in Restenosis After Carotid Injury
Szöcs, K., Lassegue, B. P., Sorescu, D., Hilenski, L. L., Valppu, L., Couse, T. L., Wilcox, J. N., Quinn, M. T., Lambeth, J. D., & Griendling, K. K. (2002) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/hq0102.102189 · Cited by 444 · see citing works
Sturrock, A., Cahill, B., Norman, K., Huecksteadt, T. P., Hill, K., Sanders, K., Karwande, S. V., Stringham, J. C., Bull, D. A., Gleich, M., et al. (2006) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.00269.2005 · Cited by 402 · see citing works
Self-citationHypoxia-induced reactive oxygen species formation in skeletal muscle
Clanton, T. L. (2007) · Journal of Applied Physiology · doi:10.1152/japplphysiol.01298.2006 · Cited by 401 · see citing works
Signaling Molecules in Nonfamilial Pulmonary Hypertension
Du, L., Sullivan, C. C., Chu, D., Cho, A. J., Kido, M., Wolf, P. L., Yuan, J. X. ‐., Deutsch, R., Jamieson, S. W., & Thistlethwaite, P. A. (2003) · New England Journal of Medicine · doi:10.1056/nejmoa021650 · Cited by 400 · see citing works
McMahon, S., Charbonneau, M., Grandmont, S., Richard, D. E., & Dubois, C. M. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m604507200 · Cited by 329 · see citing works
Mittal, M., Roth, M., König, P., Hofmann, S., Dony, E., Goyal, P., Selbitz, A.-C., SCHERMULY, R. T., Ghofrani, H. A., Kwapiszewska, G., et al. (2007) · Circulation Research · doi:10.1161/circresaha.107.148015 · Cited by 328 · see citing works
Vallet, P., Charnay, Y., Steger, K., Ogier-Denis, E., Kovari, E., Herrmann, F., Michel, J.-P., & Szanto, I. (2005) · Neuroscience · doi:10.1016/j.neuroscience.2004.12.038 · Cited by 291 · see citing works
Oxygen in mammalian tissue: methods of measurement and affinities of various reactions
Vanderkooi, J. M., Erecińska, M., & Silver, I. A. (1991) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.1991.260.6.c1131 · Cited by 279 · see citing works
Hypoxic pulmonary hypertension: role of superoxide and NADPH oxidase (gp91phox)
Liu, J. Q., Zelko, I. N., Erbynn, E. M., Sham, J. S. K., & Folz, R. J. (2005) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.00135.2005 · Cited by 275 · see citing works
Transforming Growth Factor-β Signal Transduction in Angiogenesis and Vascular Disorders
Bertolino, P., Deckers, M. M. L., Lebrin, F., & ten Dijke, P. (2005) · CHEST Journal · doi:10.1378/chest.128.6_suppl.585s · Cited by 264 · see citing works
Wedgwood, S., Dettman, R. W., & Black, S. M. (2001) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.2001.281.5.l1058 · Cited by 258 · see citing works
Leal, S. M., Liu, Q., Huang, S. S., & Huang, J. S. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.33.20572 · Cited by 255 · see citing works
Genetic basis of pulmonary arterial hypertension
Newman, J. H., Trembath, R. C., Morse, J. A., Grünig, E., Loyd, J. E., Adnot, S., Coccolo, F., Ventura, C., Phillips, J. A., Knowles, J. A., et al. (2004) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2004.02.028 · Cited by 246 · see citing works
Horowitz, J. C., Lee, D. Y., Waghray, M., Keshamouni, V. G., Thomas, P. E., Zhang, H., Cui, Z., & Thannickal, V. J. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m306248200 · Cited by 239 · see citing works
Redox‐dependent signalling by angiotensin II and vascular remodelling in hypertension
Touyz, R. M., Tabet, F., & Schiffrin, E. L. (2003) · Clinical and Experimental Pharmacology and Physiology · doi:10.1046/j.1440-1681.2003.03930.x · Cited by 236 · see citing works
Hoshikawa, Y., Ono, S., Suzuki, S., Tanita, T., Chida, M., Song, C., Noda, M., Tabata, T., Voelkel, N. F., & Fujimura, S. (2001) · Journal of Applied Physiology · doi:10.1152/jappl.2001.90.4.1299 · Cited by 233 · see citing works
Pilewski, J. M., Liu, L., Henry, A. C., Knauer, A. V., & Feghali‐Bostwick, C. A. (2005) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)62263-8 · Cited by 230 · see citing works
Increased Superoxide Generation Is Associated With Pulmonary Hypertension in Fetal Lambs
Brennan, L., Steinhorn, R. H., Wedgwood, S., Mata‐Greenwood, E., Roark, E. A., Russell, J. A., & Black, S. M. (2003) · Circulation Research · doi:10.1161/01.res.0000063424.28903.bb · Cited by 227 · see citing works
TGF‐β control of cell proliferation
Huang, S. S., & Huang, J. S. (2005) · Journal of Cellular Biochemistry · doi:10.1002/jcb.20558 · Cited by 219 · see citing works
Brown, M. R., Miller, F. J., Li, W.-G., Ellingson, A. N., Mozena, J. D., Chatterjee, P., Engelhardt, J. F., Zwacka, R. M., Oberley, L. W., Fang, X., et al. (1999) · Circulation Research · doi:10.1161/01.res.85.6.524 · Cited by 219 · see citing works
Viñals, F., & Pouysségur, J. (2001) · Molecular and Cellular Biology · doi:10.1128/mcb.21.21.7218-7230.2001 · Cited by 191 · see citing works
Wolin, M. S., Ahmad, M., & Gupte, S. A. (2005) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.00060.2005 · Cited by 188 · see citing works
PI3K is required for proliferation and migration of human pulmonary vascular smooth muscle cells
Goncharova, E. A., Ammit, A. J., Irani, C., et al. (2002) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.00010.2002 · Cited by 180 · see citing works
Löfqvist, C., Chen, J., Connor, K. M., et al. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0702031104 · Cited by 175 · see citing works
McMahon, S., Grondin, F., McDonald, P. P., Richard, D. E., & Dubois, C. M. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m413248200 · Cited by 170 · see citing works
Djordjevic, T., BelAiba, R. S., Bonello, S., Pfeilschifter, J. M., Hess, J., & Görlach, A. (2004) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/01.atv.0000154279.98244.eb · Cited by 164 · see citing works
Nylander, K., Coates, P. J., & Hall, P. A. (2000) · International Journal of Cancer · doi:10.1002/1097-0215(20000801)87:3 · Cited by 142 · see citing works
Chang, K. H., Chan‐Ling, T., McFarland, E. L., Afzal, A., Pan, H., Baxter, L. C., Shaw, L. C., Caballero, S., Sengupta, N., Calzi, S. L., et al. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0702072104 · Cited by 135 · see citing works
Djordjevic, T., Pogrebniak, A., BelAiba, R. S., Bonello, S., Wotzlaw, C., Acker, H., Hess, J., & Görlach, A. (2004) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2004.09.036 · Cited by 134 · see citing works
Sturrock, A., Huecksteadt, T. P., Norman, K. G., Sanders, K. A., Murphy, T. M., Chitano, P., Wilson, K. M., Hoidal, J. R., & Kennedy, T. P. (2007) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.00430.2006 · Cited by 132 · see citing works
Self-citationDéliot, N., Hernando, N., Horst-Liu, Z., Gisler, S. M., Capuano, P., Wagner, C. A., Bacic, D., O'Brien, S., Biber, J., & Murer, H. (2005) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00456.2004 · Cited by 130 · see citing works
Leal, S. M., Huang, S. S., & Huang, J. S. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.10.6711 · Cited by 106 · see citing works
Hypoxic constriction and reactive oxygen species in porcine distal pulmonary arteries
Liu, J. Q., Sham, J. S. K., Shimoda, L. A., Kuppusamy, P., & Sylvester, J. T. (2003) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.00337.2002 · Cited by 105 · see citing works
Chen, Y.-F., Feng, J., Li, P., et al. (2005) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00595.2005 · Cited by 104 · see citing works
Reactive oxygen species alter contractile properties of pulmonary arterial smooth muscle
Rhoades, R. A., Packer, C. S., Roepke, D. A., Jin, N., & Meiss, R. A. (1990) · Canadian Journal of Physiology and Pharmacology · doi:10.1139/y90-241 · Cited by 102 · see citing works
Liu, Y., & Fanburg, B. L. (2005) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/rcmb.2005-0163oc · Cited by 98 · see citing works
Brar, S. S., Kennedy, T. P., Whorton, A. R., Murphy, T. M., Chitano, P., & Hoidal, J. R. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.28.20017 · Cited by 93 · see citing works
Self-citationCharacterization of the expression of the hypoxia‐induced genes neuritin, TXNIP and IGFBP3 in cancer
Jan, S. L., Meur, N. L., Cazes, A., Philippe, J., Cunff, M. L., Leger, J. J., Corvol, P. L., & Germain, S. (2006) · FEBS Letters · doi:10.1016/j.febslet.2006.05.011 · Cited by 93 · see citing works
IGFBP-3 mediates TGF-β1-induced cell growth in human airway smooth muscle cells
Cohen, P., Rajah, R., Rosenbloom, J., et al. (2000) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.2000.278.3.l545 · Cited by 73 · see citing works
Metabolic, but not respiratory, acidosis increases bone PGE2levels and calcium release
Bushinsky, D. A., Parker, W. R., Alexander, K. M., & Krieger, N. S. (2001) · American Journal of Physiology-Renal Physiology · doi:10.1152/ajprenal.0355.2000 · Cited by 72 · see citing works
Gerasimovskaya, E. V., Tucker, D. A., & Stenmark, K. R. (2004) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00715.2004 · Cited by 69 · see citing works
Williams, J. T., & Payne, J. A. (2004) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00005.2004 · Cited by 68 · see citing works
Tucci, M., Nygard, K. L., Tanswell, B., Farber, H. W., Hill, D., & Han, V. (1998) · Journal of Endocrinology · doi:10.1677/joe.0.1570013 · Cited by 55 · see citing works
Sheares, K. K. K., Jeffery, T. K., Long, L., Yang, X., & Morrell, N. W. (2004) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.00012.2004 · Cited by 54 · see citing works
THE PATHOLOGY OF PULMONARY ARTERY HYPERTENSION
Meyrick, B. O. (2001) · Clinics in Chest Medicine · doi:10.1016/s0272-5231(05)70279-3 · Cited by 46 · see citing works
Superoxide in the pulmonary circulation
Demiryürek, A. T. (1999) · Pharmacology & Therapeutics · doi:10.1016/s0163-7258(99)00041-8 · Cited by 44 · see citing works
Lee, W., Wang, G., Yang, X.-L., et al. (1999) · Endocrine · doi:10.1385/endo:11:2:181 · Cited by 32 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Reactive Oxygen Species in Inflammation and Tissue Injury
Mittal, M., Siddiqui, M. R., Tran, K., Reddy, S. P., & Malik, A. B. (2014) · Antioxidants & Redox Signaling · doi:10.1089/ars.2012.5149 · Cited by 4,897 · see citing works
Combating oxidative stress in vascular disease: NADPH oxidases as therapeutic targets
Drummond, G. R., Selemidis, S., Griendling, K. K., & Sobey, C. G. (2011) · Nature Reviews Drug Discovery · doi:10.1038/nrd3403 · Cited by 899 · see citing works
NADPH Oxidases: Functions and Pathologies in the Vasculature
Lassègue, B., & Griendling, K. K. (2010) · Arteriosclerosis, Thrombosis, and Vascular Biology · doi:10.1161/atvbaha.108.181610 · Cited by 592 · see citing works
Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation
Tejero, J., Shiva, S., & Gladwin, M. T. (2019) · Physiological Reviews · doi:10.1152/physrev.00036.2017 · Cited by 541 · see citing works
The nox4 inhibitor gkt137831 attenuates hypoxia-induced pulmonary vascular cell proliferation
Green, D. E., Murphy, T. C., Kang, B.-Y., Kleinhenz, J. M., Szyndralewiez, C., Page, P., Sutliff, R. L., & Hart, C. M. (2012) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/rcmb.2011-0418oc · Cited by 146 · see citing works
- Authors
- Ismail, S., Sturrock, A., Wu, P., Cahill, B., Norman, K., Huecksteadt, T., Sanders, K., Kennedy, T., & Hoidal, J.
- Affiliations
- University of Utah (US)
- Venue
- American Journal of Physiology-Lung Cellular and Molecular Physiology
- Publisher
- American Physiological Society
- Published
- 2009-03
- Volume
- 296
- Issue
- 3
- Pages
- L489-L499
- ISSN
- 1040-0605 (ISSN-L)
- 1522-1504
- PMC
- PMC2660216
- OpenAlex
- W2141997908
- Cited by
- 177
- References
- 73
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 4 · 2023: 3 · 2022: 5 · 2021: 7 · 2020: 3 · 2019: 12 · 2018: 11 · 2017: 14 · 2016: 14 · 2015: 16 · 2014: 13 · 2013: 17 · 2012: 21
- FWCI
- 9.52
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- American Journal of Physiology-Lung Cellular and Molecular Physiology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Heart, Lung, and Blood Institute (R01HL067281, HL67281)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Pulmonary Hypertension Research and Treatments
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Keywords
- NOX4, pulmonary artery smooth muscle cells, hypoxia, cell proliferation, pulmonary arterial hypertension, autocrine signaling, TGF-β1, insulin-like growth factor binding protein-3, NADPH oxidase, reactive oxygen species, PI3K/Akt signaling, Smad signaling, pulmonary vascular remodeling, diphenyleneiodonium
- MeSH terms
- NADPH Oxidase 4, Cells, Cultured, Humans, Models, Biological, Pulmonary Artery, Signal Transduction, Cell Hypoxia, Gene Expression, Reactive Oxygen Species, Insulin-Like Growth Factor Binding Proteins, Insulin-Like Growth Factor Binding Protein 3, NADPH Oxidases, Phosphatidylinositol 3-Kinases, Autocrine Communication, Myocytes, Smooth Muscle, RNA Interference, Cell Proliferation, Proto-Oncogene Proteins c-akt, Transforming Growth Factor beta1
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
