Abstract
Pulmonary hypertension (PH) is characterized by increased vasoconstriction and smooth muscle cell hyperplasia driving pathological vascular remodeling of arterial vessels. In this short review, we discuss the primary source of reactive oxygen species (ROS) and nitric oxide (NO) relevant to PH and the mechanism by which dysregulation of their production contributes to PH. Specifically, hypoxia-induced PH is associated with diminished endothelial nitric oxide synthase (eNOS)-derived NO production and increased production of superoxide (O2 •-) through eNOS uncoupling and defective mitochondrial respiration. This drives the inhibition of the NO/soluble guanylate cyclase (sGC) pathway and activation of the transcription factor hypoxia-inducible factor-1α (HIF-1α) with consequential dysregulation of the pulmonary vasculature. Therapeutics aimed at increasing NO or cGMP bioavailabilities are amenable to hypoxia disease-induced PH. Similarly, strategies targeting HIF-1α are now considered. Overall, pulmonary hypertension including hypoxia-induced PH offers unique opportunities for the rational development of therapeutics centered on modulating redox signaling.
Keywords
This is a preview of subscription content, log in via an institution.
Buying options
Tax calculation will be finalised at checkout
Purchases are for personal use only
Learn about institutional subscriptionsReferences
Naeije, R. (2005). Pulmonary hypertension and right heart failure in chronic obstructive pulmonary disease. Proceedings of the American Thoracic Society, 2, 20–22.
Prabhakar, N. R., & Semenza, G. L. (2012). Adaptive and maladaptive cardiorespiratory responses to continuous and intermittent hypoxia mediated by hypoxia-inducible factors 1 and 2. Physiological Reviews, 92, 967–1003.
Ball, M. K., Waypa, G. B., Mungai, P. T., Nielsen, J. M., Czech, L., Dudley, V. J., et al. (2014). Regulation of hypoxia-induced pulmonary hypertension by vascular smooth muscle hypoxia-inducible factor-1alpha. American Journal of Respiratory and Critical Care Medicine, 189, 314–324.
Bonnet, S., Michelakis, E. D., Porter, C. J., Andrade-Navarro, M. A., Thebaud, B., Bonnet, S., et al. (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.
Moncada, S., Palmer, R. M. J., & Higgs, E. A. (1991). Nitric oxide: Physiology, pathophysiology, and pharmacology. Pharmacological Reviews, 43(2), 109–142.
Nathan, C., & Xie, Q.-W. (1994). Nitric oxide synthases: Roles, tolls, and controls. Cell, 78, 915–918.
Feelisch, M., Rassaf, T., Mnaimneh, S., Singh, N., Bryan, N. S., Jourd’Heuil, D., et al. (2002). Concomitant S-, N-, and heme-nitros(yl)ation in biological tissues and fluids: Implications for the fate of NO in vivo. The FASEB Journal, 16, 1775–1785.
Grisham, M. B., Jourd'Heuil, D., & Wink, D. A. (1999). Nitric oxide. I. Physiological chemistry of nitric oxide and its metaolites: Implication in inflammation. The American Journal of Physiology, 39, G315–G321.
Foster, M. W., McMahon, T. J., & Stamler, J. S. (2003). S-nitrosylation in health and disease. Trends in Molecular Medicine, 9, 160–168.
Zweier, J. L., Wang, P., Samouilov, A., & Kuppusamy, P. (1995). Enzyme-independent formation of nitric oxide in biological tissues. Nature Medicine, 1, 804–809.
Huang, Z., Shiva, S., Kim-Shapiro, D. B., Patel, R. P., Ringwood, L. A., Irby, C. E., et al. (2005). Enzymatic function of hemoglobin as a nitrite reductase that produces NO under allosteric control. Journal of Clinical Investigation, 118, 2099–2107.
Rassaf, T., Totzeck, M., Hendgen-Cotta, U. B., Shiva, S., Heusch, G., & Kelm, M. (2014). Circulating nitrite contributes to cardioprotection by remote ischemic preconditioning. Circulation Research, 114, 1601–1610.
Tiso, M., Tejero, J., Basu, S., Azarov, I., Wang, X., Simplaceanu, V., et al. (2011). Human neuroglobin functions as a redox-regulated nitrite reductase. The Journal of Biological Chemistry, 286, 18277–18289.
Li, H., Hemann, C., Abdelghany, T. M., El-Mahdy, M. A., & Zweier, J. L. (2012). Characterization of the mechanism and magnitude of cytoglobin-mediated nitrite reduction and nitric oxide generation under anaerobic conditions. The Journal of Biological Chemistry, 287, 36623–36633.
Li, H., Samouilov, A., Liu, X., & Zweier, J. L. (2001). Characterization of the magnitude and kinetics of xanthine oxidase-catalyzed nitrite reduction. The Journal of Biological Chemistry, 276, 24482–24489.
Wang, J., Krizowski, S., Fischer-Schrader, K., Niks, D., Tejero, J., Sparacino-Watkins, C., et al. (2015). Sulfite oxidase catalyzes single-electron transfer at molybdenum domain to reduce nitrite to nitric oxide. Antioxidants & Redox Signaling, 23, 283–294.
Sparacino-Watkins, C. E., Tejero, J., Sun, B., Gauthier, M. C., Thomas, J., Ragireddy, V., et al. (2014). Nitrite reductase and nitric-oxide synthase activity of the mitochondrial molybdopterin enzymes mARC1 and mARC2. The Journal of Biological Chemistry, 289, 10345–10358.
Beckman, J. S., Beckman, T. W., Chen, J., Marshall, P. A., & Freeman, B. A. (1990). Apparent hydroxyl radical production by peroxynitrite: Implications for endothelial injury from nitric oxide and superoxide. Proceedings of the National Academy of Sciences of the United States of America, 87, 1620–1624.
Beckman, J. S., Ischiropoulos, H., Zhu, L., van der Woerd, M., Smith, C., Chen, J., et al. (1992). Kinetics of superoxide dismutase- and iron-catalyzed nitration of phenolics by peroxynitrite. Archives of Biochemistry and Biophysics, 298, 438–445.
Gow, A. J., Buerk, D. G., & Ischiropoulos, H. (1997). A novel reaction mechanism for the formation of S-nitrosothiol in vivo. The Journal of Biological Chemistry, 272, 2841–2845.
Denicola, A., Freeman, B. A., Trujillo, M., & Radi, R. (1996). Peroxynitrite reaction with carbon dioxide/bicarbonate kinetics and influence on peroxynitrite-mediated oxidations. Archives of Biochemistry and Biophysics, 333, 49–58.
Beckman, J. S., & Koppenol, W. H. (1996). Nitric oxide, superoxide, and peroxynitrite; the good, the bad, and the ugly. The American Journal of Physiology, 271, C1424–C1437.
Fagan, K. A., Fouty, B. W., Tyler, R. C., Morris, K. G., Jr., Hepler, L. K., Sato, K., et al. (1999). The pulmonary circulation of homozygous or heterozygous eNOS-null mice is hyperresponsive to mild hypoxia. The Journal of Clinical Investigation, 103, 291–299.
Kharitonov, S. A., Cailes, J. B., Black, C. M., du Bois, R. M., & Barnes, P. J. (1997). Decreased nitric oxide in the exhaled air of patients with systemic sclerosis with pulmonary hypertension. Thorax, 52, 1051–1055.
Quinlan, T. R., Li, D., Laubach, V. E., Shesely, E. G., Zhou, N., & Johns, R. A. (2000). eNOS-deficient mice show reduced pulmonary vascular proliferation and remodeling to chronic hypoxia. American Journal of Physiology—Lung Cellular and Molecular Physiology, 279, L641–L650.
Xue, C., & Johns, R. A. (1995). Endothelial nitric oxide synthase in the lungs of patients with pulmonary hypertension. The New England Journal of Medicine, 333, 1642–1644.
Giaid, A., & Saleh, D. (1995). Reduced expression of endothelial nitric oxide synthase in the lungs of patients with pulmonary hypertension. The New England Journal of Medicine, 333, 214–221.
Zhao, Y. Y., Zhao, Y. D., Mirza, M. K., Huang, J. H., Potula, H. H., Vogel, S. M., et al. (2009). Persistent eNOS activation secondary to caveolin-1 deficiency induces pulmonary hypertension in mice and humans through PKG nitration. The Journal of Clinical Investigation, 119, 2009–2018.
Block, E. R., Herrera, H., & Couch, M. (1995). Hypoxia inhibits L-arginine uptake by pulmonary artery endothelial cells. The American Journal of Physiology, 269, L574–L580.
Xu, W., Kaneko, F. T., Zheng, S., Comhair, S. A., Janocha, A. J., Goggans, T., et al. (2004). Increased arginase II and decreased NO synthesis in endothelial cells of patients with pulmonary arterial hypertension. The FASEB Journal, 18, 1746–1748.
Landmesser, U., Dikalov, S., Price, S. R., McCann, L., Fukai, T., Holland, S. M., et al. (2003). Oxidation of tetrahydrobiopterin leads to uncoupling of endothelial cell nitric oxide synthase in hypertension. The Journal of Clinical Investigation, 111, 1201–1209.
Tsugu, T., Murata, M., Kawakami, T., Kataoka, M., Nagatomo, Y., Tsuruta, H., et al. (2016). Amelioration of right ventricular function after hybrid therapy with riociguat and balloon pulmonary angioplasty in patients with chronic thromboembolic pulmonary hypertension. International Journal of Cardiology, 221, 227–229.
Wardle, A. J., Seager, M. J., Wardle, R., Tulloh, R. M., & Gibbs, J. S. (2016). Guanylate cyclase stimulators for pulmonary hypertension. Cochrane Database of Systematic Reviews, 8, CD011205.
Benza, R., Mathai, S., & Nathan, S. D. (2016). sGC stimulators: Evidence for riociguat beyond groups 1 and 4 pulmonary hypertension. Respiratory Medicine, 122, S28–S34.
Galie, N., Brundage, B. H., Ghofrani, H. A., Oudiz, R. J., Simonneau, G., Safdar, Z., et al. (2009). Tadalafil therapy for pulmonary arterial hypertension. Circulation, 119, 2894–2903.
Baliga, R. S., Milsom, A. B., Ghosh, S. M., Trinder, S. L., Macallister, R. J., Ahluwalia, A., et al. (2012). Dietary nitrate ameliorates pulmonary hypertension: Cytoprotective role for endothelial nitric oxide synthase and xanthine oxidoreductase. Circulation, 125, 2922–2932.
Pankey, E. A., Badejo, A. M., Casey, D. B., Lasker, G. F., Riehl, R. A., Murthy, S. N., et al. (2012). Effect of chronic sodium nitrite therapy on monocrotaline-induced pulmonary hypertension. Nitric Oxide, 27, 1–8.
Zuckerbraun, B. S., Shiva, S., Ifedigbo, E., Mathier, M. A., Mollen, K. P., Rao, J., et al. (2010). Nitrite potently inhibits hypoxic and inflammatory pulmonary arterial hypertension and smooth muscle proliferation via xanthine oxidoreductase-dependent nitric oxide generation. Circulation, 121, 98–109.
Simon, M. A., Vanderpool, R. R., Nouraie, M., Bachman, T. N., White, P. M., Sugahara, M., et al. (2016). Acute hemodynamic effects of inhaled sodium nitrite in pulmonary hypertension associated with heart failure with preserved ejection fraction. JCI Insight, 1, e89620.
Waypa, G. B., Smith, K. A., & Schumacker, P. T. (2016). O2 sensing, mitochondria and ROS signaling: The fog is lifting. Molecular Aspects of Medicine, 47–48, 76–89.
Ryan, J. J., Marsboom, G., Fang, Y. H., Toth, P. T., Morrow, E., Luo, N., et al. (2013). PGC1alpha-mediated mitofusin-2 deficiency in female rats and humans with pulmonary arterial hypertension. American Journal of Respiratory and Critical Care Medicine, 187, 865–878.
Thompson, C. B. (2016). Into thin air: How we sense and respond to Hypoxia. Cell, 167, 9–11.
Marshall, C., Mamary, A. J., Verhoeven, A. J., & Marshall, B. E. (1996). Pulmonary artery NADPH-oxidase is activated in hypoxic pulmonary vasoconstriction. American Journal of Respiratory Cell and Molecular Biology, 15, 633–644.
Chandel, N. S., Maltepe, E., Goldwasser, E., Mathieu, C. E., Simon, M. C., & Schumacker, P. T. (1998). Mitochondrial reactive oxygen species trigger hypoxia-induced transcription. Proceedings of the National Academy of Sciences of the United States of America, 95, 11715–11720.
Schroedl, C., McClintock, D. S., Budinger, G. R., & Chandel, N. S. (2002). Hypoxic but not anoxic stabilization of HIF-1alpha requires mitochondrial reactive oxygen species. American Journal of Physiology—Lung Cellular and Molecular Physiology, 283, L922–L931.
Mansfield, K. D., Guzy, R. D., Pan, Y., Young, R. M., Cash, T. P., Schumacker, P. T., et al. (2005). Mitochondrial dysfunction resulting from loss of cytochrome c impairs cellular oxygen sensing and hypoxic HIF-alpha activation. Cell Metabolism, 1, 393–399.
Waypa, G. B., Marks, J. D., Guzy, R., Mungai, P. T., Schriewer, J., Dokic, D., et al. (2010). Hypoxia triggers subcellular compartmental redox signaling in vascular smooth muscle cells. Circulation Research, 106, 526–535.
Waypa, G. B., Marks, J. D., Guzy, R. D., Mungai, P. T., Schriewer, J. M., Dokic, D., et al. (2013). Superoxide generated at mitochondrial complex III triggers acute responses to hypoxia in the pulmonary circulation. American Journal of Respiratory and Critical Care Medicine, 187, 424–432.
Shimoda, L. A., & Semenza, G. L. (2011). HIF and the lung: Role of hypoxia-inducible factors in pulmonary development and disease. American Journal of Respiratory and Critical Care Medicine, 183, 152–156.
Kamura, T., Sato, S., Iwai, K., Czyzyk-Krzeska, M., Conaway, R. C., & Conaway, J. W. (2000). Activation of HIF1alpha ubiquitination by a reconstituted von Hippel-Lindau (VHL) tumor suppressor complex. Proceedings of the National Academy of Sciences of the United States of America, 97, 10430–10435.
Maxwell, P. H., Wiesener, M. S., Chang, G. W., Clifford, S. C., Vaux, E. C., Cockman, M. E., et al. (1999). The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature, 399, 271–275.
Ivan, M., Kondo, K., Yang, H., Kim, W., Valiando, J., Ohh, M., et al. (2001). HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: Implications for O2 sensing. Science, 292, 464–468.
Epstein, A. C., Gleadle, J. M., McNeill, L. A., Hewitson, K. S., O'Rourke, J., Mole, D. R., et al. (2001). C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell, 107, 43–54.
Ivan, M., Haberberger, T., Gervasi, D. C., Michelson, K. S., Gunzler, V., Kondo, K., et al. (2002). Biochemical purification and pharmacological inhibition of a mammalian prolyl hydroxylase acting on hypoxia-inducible factor. Proceedings of the National Academy of Sciences of the United States of America, 99, 13459–13464.
Chua, Y. L., Dufour, E., Dassa, E. P., Rustin, P., Jacobs, H. T., Taylor, C. T., et al. (2010). Stabilization of hypoxia-inducible factor-1alpha protein in hypoxia occurs independently of mitochondrial reactive oxygen species production. The Journal of Biological Chemistry, 285, 31277–31284.
Brunelle, J. K., Bell, E. L., Quesada, N. M., Vercauteren, K., Tiranti, V., Zeviani, M., et al. (2005). Oxygen sensing requires mitochondrial ROS but not oxidative phosphorylation. Cell Metabolism, 1, 409–414.
Guzy, R. D., Hoyos, B., Robin, E., Chen, H., Liu, L., Mansfield, K. D., et al. (2005). Mitochondrial complex III is required for hypoxia-induced ROS production and cellular oxygen sensing. Cell Metabolism, 1, 401–408.
Shimoda, L. A., Manalo, D. J., Sham, J. S., Semenza, G. L., & Sylvester, J. T. (2001). Partial HIF-1alpha deficiency impairs pulmonary arterial myocyte electrophysiological responses to hypoxia. American Journal of Physiology—Lung Cellular and Molecular Physiology, 281, L202–L208.
Kline, D. D., Peng, Y. J., Manalo, D. J., Semenza, G. L., & Prabhakar, N. R. (2002). Defective carotid body function and impaired ventilatory responses to chronic hypoxia in mice partially deficient for hypoxia-inducible factor 1 alpha. Proceedings of the National Academy of Sciences of the United States of America, 99, 821–826.
Shimoda, L. A., Fallon, M., Pisarcik, S., Wang, J., & Semenza, G. L. (2006). HIF-1 regulates hypoxic induction of NHE1 expression and alkalinization of intracellular pH in pulmonary arterial myocytes. American Journal of Physiology—Lung Cellular and Molecular Physiology, 291, L941–L949.
Yu, A. Y., Shimoda, L. A., Iyer, N. V., Huso, D. L., Sun, X., McWilliams, R., et al. (1999). Impaired physiological responses to chronic hypoxia in mice partially deficient for hypoxia-inducible factor 1alpha. The Journal of Clinical Investigation, 103, 691–696.
Popov, S., Takemori, H., Tokudome, T., Mao, Y., Otani, K., Mochizuki, N., et al. (2014). Lack of salt-inducible kinase 2 (SIK2) prevents the development of cardiac hypertrophy in response to chronic high-salt intake. PloS One, 9, e95771.
Morrell, N. W., Adnot, S., Archer, S. L., Dupuis, J., Jones, P. L., MacLean, M. R., et al. (2009). Cellular and molecular basis of pulmonary arterial hypertension. Journal of the American College of Cardiology, 54, S20–S31.
Shimoda, L. A., Sham, J. S., Shimoda, T. H., & Sylvester, J. T. (2000). L-type Ca(2+) channels, resting [Ca(2+)](i), and ET-1-induced responses in chronically hypoxic pulmonary myocytes. American Journal of Physiology—Lung Cellular and Molecular Physiology, 279, L884–L894.
Wang, J., Weigand, L., Lu, W., Sylvester, J. T., Semenza, G. L., & Shimoda, L. A. (2006). Hypoxia inducible factor 1 mediates hypoxia-induced TRPC expression and elevated intracellular Ca2+ in pulmonary arterial smooth muscle cells. Circulation Research, 98, 1528–1537.
Archer, S. L., Souil, E., Dinh-Xuan, A. T., Schremmer, B., Mercier, J. C., El Yaagoubi, A., et al. (1998). Molecular identification of the role of voltage-gated K+ channels, Kv1.5 and Kv2.1, in hypoxic pulmonary vasoconstriction and control of resting membrane potential in rat pulmonary artery myocytes. The Journal of Clinical Investigation, 101, 2319–2330.
Reeve, H. L., Michelakis, E., Nelson, D. P., Weir, E. K., & Archer, S. L. (2001). Alterations in a redox oxygen sensing mechanism in chronic hypoxia. Journal of Applied Physiology, 90, 2249–2256.
Yuan, X. J., Wang, J., Juhaszova, M., Gaine, S. P., & Rubin, L. J. (1998). Attenuated K+ channel gene transcription in primary pulmonary hypertension. Lancet, 351, 726–727.
Zhang, H., Qian, D. Z., Tan, Y. S., Lee, K., Gao, P., Ren, Y. R., et al. (2008). Digoxin and other cardiac glycosides inhibit HIF-1alpha synthesis and block tumor growth. Proceedings of the National Academy of Sciences of the United States of America, 105, 19579–19586.
Abud, E. M., Maylor, J., Undem, C., Punjabi, A., Zaiman, A. L., Myers, A. C., et al. (2012). Digoxin inhibits development of hypoxic pulmonary hypertension in mice. Proceedings of the National Academy of Sciences of the United States of America, 109, 1239–1244.
Michelakis, E. D., McMurtry, M. S., Wu, X. C., Dyck, J. R., Moudgil, R., Hopkins, T. A., et al. (2002). Dichloroacetate, a metabolic modulator, prevents and reverses chronic hypoxic pulmonary hypertension in rats: Role of increased expression and activity of voltage-gated potassium channels. Circulation, 105, 244–250.
Acknowledgment
This work was supported in part by National Institutes of health grant K01HL130704 (A. Jaitovich) and American Heart Association grant AHA-16GRNT31280002 (D. Jourd’heuil). Figures were produced using Servier Medical Art (www.servier.com).
Author information
Authors and Affiliations
Corresponding authors
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2017 Springer International Publishing AG
About this chapter
Cite this chapter
Jaitovich, A., Jourd’heuil, D. (2017). A Brief Overview of Nitric Oxide and Reactive Oxygen Species Signaling in Hypoxia-Induced Pulmonary Hypertension. In: Wang, YX. (eds) Pulmonary Vasculature Redox Signaling in Health and Disease. Advances in Experimental Medicine and Biology, vol 967. Springer, Cham. https://doi.org/10.1007/978-3-319-63245-2_6
Download citation
DOI: https://doi.org/10.1007/978-3-319-63245-2_6
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-319-63244-5
Online ISBN: 978-3-319-63245-2
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)