− OONO
2001; Lippincott Williams & Wilkins; Volume: 89; Issue: 4 Linguagem: Lituano
10.1161/res.89.4.295
ISSN1524-4571
Autores Tópico(s)Nitric Oxide and Endothelin Effects
ResumoHomeCirculation ResearchVol. 89, No. 4−OONO Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUB−OONORebounding From Nitric Oxide Joseph S. Beckman Joseph S. BeckmanJoseph S. Beckman From the Linus Pauling Institute, Department of Biochemistry and Biophysics, Oregon State University, Corvallis, Oreg. Originally published3 Apr 2018https://doi.org/10.1161/res.89.4.295Circulation Research. 2001;89:295–297Inhaled nitric oxide is an elegantly simple therapy for idiopathic pulmonary hypertension. Breathing small amounts of nitric oxide directly activates guanylyl cyclase in pulmonary resistance vessels to counteract hypertension. In patients who respond to inhaled nitric oxide, either the endogenous synthesis of nitric oxide is not sufficient to overcome the hypertensive stress or nitric oxide is being inactivated too rapidly to act on guanylate cyclase. Certainly, both processes could be operating simultaneously.Although nitric oxide has a reputation for being highly toxic, in reality the risk of toxicity with inhaled nitric oxide is minor because nitric oxide itself is unreactive with most biological molecules and the amounts administered are low enough to minimize the formation of nitrogen dioxide. Nitric oxide becomes toxic when converted to secondary reactive nitrogen species. Nitric oxide itself is swept away from the vasculature by rapid reactions with hemoglobin. In the high oxygen environment of the lung, nitric oxide will also not significantly inhibit mitochondrial respiration. By now, many patients have been breathing nitric oxide for weeks and even months without overt harm.However, sudden termination of inhaled nitric oxide occasionally causes a potentially life-threatening hypertensive rebound, even when treated for a few hours. Hypertensive rebound can occur in individuals who showed no initial vasodilation in response to nitric oxide. In this issue of Circulation Research, Wedgwood et al1 have shown that endothelin, the most potent vasoconstrictor known, may contribute to rebound hypertension by inducing superoxide synthesis in the pulmonary vasculature. The increased flux of superoxide will react with nitric oxide to form peroxynitrite. The authors further show that endothelial nitric oxide synthase becomes nitrated on tyrosine, and the endogenous synthesis of nitric oxide by endothelium is decreased. Misfolding of endothelial nitric oxide synthase can cause the enzyme itself to produce superoxide.2–4 Activation of these pathways could not only contribute to rebound hypertension but could also be a contributing factor for the failure of nitric oxide therapy to affect pulmonary hypertension in unresponsive patients.Peroxynitrite is formed by the diffusion-limited radical-radical reaction between superoxide and nitric oxide. Diffusion-limited is simply a chemist's jargon implying that every time nitric oxide bumps into superoxide (which is controlled by diffusion), the two produce peroxynitrite. Because nitric oxide is 1000 times smaller than copper, zinc superoxide dismutase (SOD), it diffuses faster and therefore reacts with superoxide at least 10 times faster than SOD can possibly scavenge superoxide.5,6 Because of this competitive advantage, a substantial fraction of any superoxide produced in lung will produce peroxynitrite when micromolar nitric oxide is being inhaled.Peroxynitrite is itself a strong oxidant and when protonated will produce the strongly oxidizing radicals hydroxyl radical and nitrogen dioxide.7,8 Peroxynitrite reacts rapidly with carbon dioxide to form nitrogen dioxide and bicarbonate radical, which can be even more damaging than the overly promiscuous hydroxyl radical. Although peroxynitrite is thermodynamically a potent oxidant, it tends to react rather selectively with many biological molecules. The surprising result is that peroxynitrite can activate a variety of signaling pathways, which tend to be proinflammatory and hypertensive (see Figure). Download figureDownload PowerPointInhaled nitric oxide will rapidly diffuse through the pulmonary epithelium to activate guanylyl cyclase in vascular smooth muscle. It will further diffuse through endothelium to react with hemoglobin, principally forming met-hemoglobin and nitrate. However, when tissues produce superoxide, some of the nitric oxide will be converted to peroxynitrite that will cause some tissue damage. Certain proinflammatory pathways are particularly reactive to peroxynitrite. Consequently, peroxynitrite can increase the formation of PGH2 from arachidonate (AA) by stimulating cyclooxygenase while decreasing the formation of prostacyclin by inhibiting prostacyclin synthase (PGIS). Peroxynitrite can also increase the phosphorylation and activation of JNK. Peroxynitrite promotes the inflammatory synthesis of prostaglandin. The conjugate acid of peroxynitrite (ONOOH) plays an important role in vivo in the activation of cyclooxygenase by providing the peroxide tone necessary for enzyme activity. The non–heme iron in cyclooxygenase must initially be oxidized to an unstable and reactive ferryl state to be able to oxidize arachidonic acid. Marnett and colleagues have shown that peroxynitrite is the major peroxide responsible for activating cyclooxygenase in vivo.9,10 The product of cyclooxygenase, PGH2, is usually converted by prostacyclin synthase to the vasodilatory and antithrombotic prostaglandin (PGI2). Curiously, prostacyclin synthase is itself exceptionally susceptible to attack by peroxynitrite, which appears to inactivate the enzyme by nitration of a critical tyrosine residue.11,12Accumulating PGH2 from cyclooxygenase can activate thromboxane receptors with similar potency as thromboxane itself. Thus, the reaction of superoxide with nitric oxide in the vasculature can help subvert the principal vasodilating mechanisms of endothelium into becoming strongly vasoconstricting.Peroxynitrite induces longer-lasting changes in the vasculature and the immune system by deactivating anti-inflammatory agents as well as activating other stress-related signaling cascades. Peroxynitrite is particularly effective with inactivated tyrosine kinases such as CD45.13 CD45 is a JAK phosphatase that appears to have a central role in downregulating proinflammatory responses.14 The binding site for the phosphate on phosphotyrosine can easily accommodate peroxynitrite and orient it to attack the crucial sulfhydryl in the active site. Cultured endothelium responds to increased shear stress by activating NADPH oxidase and endothelial nitric oxide synthesis.15 The resulting endogenous formation of peroxynitrite activates c-Jun-NH2-terminal kinase (JNK), which induces a wide range of stress-related responses. The peroxynitrite formation in endothelium does not induce apoptosis. However, peroxynitrite-induced activation of JNK does induce apoptosis in neurons. Peroxynitrite is acting far upstream to activate apoptosis in these studies, and activation of the antiapoptotic serine/threonine kinase Akt (protein kinase B) is sufficient to block cell death.16–19 Peroxynitrite may also be promoting intracellular release of acidic fibroblast growth factor, which can induce vascular remodeling and fibroblast proliferation.20While peroxynitrite is acting like a signaling molecule and acting surprisingly far upstream, it is simultaneously oxidizing multiple targets within a cell. DNA, RNA, proteins, and lipids will suffer some extent of oxidative damage at the same time as peroxynitrite is affecting signaling pathways. Why would nature make use of such a damaging agent?Peroxynitrite and other oxidants are well known to be important microbicidal agents produced by phagocytes.21–23 However, peroxynitrite may also be an important adaptive mechanism to limit trauma-induced bleeding and the spread of infectious agents. Nitric oxide is almost continuously being produced to modulate vasoconstriction and to reduce platelet adhesion. By activating the production of superoxide, nitric oxide can simultaneously be rapidly inactivated and turned into a potent antimicrobial agent. By having functional groups that are particularly sensitive to peroxynitrite, certain proteins can sense peroxynitrite and thereby reinforce proinflammatory cascades. Resistance to infection is an overwhelming survival factor that is strongly favored by evolution. The collateral damage may be a small price to pay for surviving infection from an evolutionary perspective but may be complicating our current attempts at therapeutic intervention with inhaled nitric oxide.The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.FootnotesCorrespondence to Joseph S. Beckman, Ava Helen Pauling Chair, Linus Pauling Institute, Department of Biochemistry and Biophysics, Oregon State University, Corvallis, OR 97331. E-mail [email protected] References 1 Wedgwood S, McMullan DM, Bekker JM, Fineman JR, Black SM. Role for endothelin-1–induced superoxide and peroxynitrite production in rebound pulmonary hypertension associated with inhaled nitric oxide therapy. Circ Res. 2001; 89: 357–364.CrossrefMedlineGoogle Scholar2 Pritchard KA Jr, Groszek L, Smalley DM, Sessa WC, Wu M, Villalon P, Wolin MS, Stemerman MB. Native low-density lipoprotein increases endothelial cell nitric oxide synthase generation of superoxide anion. Circ Res. 1995; 77: 510–518.CrossrefMedlineGoogle Scholar3 Vásquez-Vivar J, Hogg N, Pritchard KA Jr, Martasek P, Kalyanaraman B. Superoxide anion formation from lucigenin: an electron spin resonance spin-trapping study. FEBS Lett. 1997; 403: 127–130.CrossrefMedlineGoogle Scholar4 Xia Y, Dawson VL, Dawson TM, Snyder SH, Zweier JL. Nitric oxide synthase generates superoxide and nitric oxide in arginine-depleted cells leading to peroxynitrite-mediated cellular injury. Proc Natl Acad Sci USA. 1996; 93: 6770–6774.CrossrefMedlineGoogle Scholar5 Beckman JS, Koppenol WH. Nitric oxide, superoxide, and peroxynitrite: the good, the bad, and the ugly. Am J Physiol. 1996; 271 (5 pt 1): C1424–C1437.CrossrefMedlineGoogle Scholar6 Kissner R, Nauser T, Bugnon P, Lye PG, Koppenol WH. Formation and properties of peroxynitrite as studied by laser flash photolysis, high-pressure stopped-flow technique, and pulse radiolysis. Chem Res Toxicol. 1997; 10: 1285–1292.CrossrefMedlineGoogle Scholar7 Beckman JS, Beckman TW, Chen J, Marshall PM, Freeman BA. Apparent hydroxyl radical production by peroxynitrite: implications for endothelial injury by nitric oxide and superoxide. Proc Natl Acad Sci USA. 1990; 87: 1620–1624.CrossrefMedlineGoogle Scholar8 Coddington JW, Hurst JK, Lymar SV. Hydroxyl radical formation during peroxynitrous acid decomposition. J Am Chem Soc. 1999; 121: 2438–2443.CrossrefGoogle Scholar9 Landino LM, Crews BC, Timmons MD, Morrow JD, Marnett LJ. Peroxynitrite, the coupling product of nitric oxide and superoxide, activates prostaglandin biosynthesis. Proc Natl Acad Sci USA. 1996; 93: 15069–15074.CrossrefMedlineGoogle Scholar10 Marnett LJ, Wright TL, Crews BC, Tannenbaum SR, Morrow JD. Regulation of prostaglandin biosynthesis by nitric oxide is revealed by targeted deletion of inducible nitric-oxide synthase. J Biol Chem. 2000; 275: 13427–13430.CrossrefMedlineGoogle Scholar11 Zou M-H, Ullrich V. Peroxynitrite formed by simultaneous generation of nitric oxide and superoxide selectively inhibits bovine aortic prostacyclin synthase. FEBS Lett. 1996; 382: 101–104.CrossrefMedlineGoogle Scholar12 Zou M, Martin C, Ullrich V. Tyrosine nitration as a mechanism of selective inactivation of prostacyclin synthase by peroxynitrite. Biol Chem Hoppe Seyler. 1997; 378: 707–713.CrossrefMedlineGoogle Scholar13 Takakura K, Beckman JS, MacMillan-Crow LA, Crow JP. Rapid and irreversible inactivation of protein tyrosine phosphatases PTP1B, CD45, and LAR by peroxynitrite. Arch Biochem Biophys. 1999; 369: 197–207.CrossrefMedlineGoogle Scholar14 Irie-Sasaki J, Sasaki T, Matsumoto W, Opavsky A, Cheng M, Welstead G, Griffiths E, Krawczyk C, Richardson CD, Aitken K, Iscove N, Koretzky G, Johnson P, Liu P, Rothstein DM, Penninger JM. CD45 is a JAK phosphatase and negatively regulates cytokine receptor signalling. Nature. 2001; 409: 349–354.CrossrefMedlineGoogle Scholar15 Go Y-M, Patel RP, Maland MC, Park H, Beckman JS, Darley-Usmar VM, Jo H. Evidence for peroxynitrite is a signaling molecule in flow-dependent activation of c-Jun NH2-terminal kinase. Am J Physiol. 1999; 277: H1647–H1653.MedlineGoogle Scholar16 Spear N, Estevez AG, Barbeito L, Beckman JS, Johnson GVW. Nerve growth factor protects PC12 cells against peroxynitrite-induced apoptosis via a mechanism dependent on phosphatidylinositol-3 kinase. J Neurochem. 1997; 69: 53–59.MedlineGoogle Scholar17 Spear N, Estevez AG, Radi R, Beckman JS. Peroxynitrite and cell signaling. In: Forman HJ, Cadenas E, eds. Oxidative Stress and Signal Transduction. New York, NY: Chapman & Hall; 1997:32–51.Google Scholar18 Spear N, Estevez AG, Johnson GVW, Bredesen DE, Thompson JA, Beckman JS. Enhancement of peroxynitrite-induced apoptosis in PC12 cells by FGF-1 and NGF requires p21Ras activation and is suppressed by Bcl-2. Arch Biochem Biophys. 1998; 356: 41–45.CrossrefMedlineGoogle Scholar19 Estévez AG, Spear N, Manuel SM, Barbeito L, Radi R, Beckman JS. Role of endogenous nitric oxide and peroxynitrite formation in the survival and death of motor neurons in culture. In: Mize R, Friedlander M, eds. Progress in Brain Research. Amsterdam, the Netherlands: Elsevier; 1998:269–280.Google Scholar20 Hicks KK, Shin JT, Opalenik SR, Thompson JA. Molecular mechanisms of angiogenesis: experimental models define cellular trafficking of FGF-1. PR Health Sci J. 1996; 15: 179–186.Google Scholar21 Babior BM. Phagocytes and oxidative stress. Am J Med. 2000; 109: 33–44.CrossrefMedlineGoogle Scholar22 Zhu L, Gunn C, Beckman JS. Bactericidal activity of peroxynitrite. Arch Biochem Biophys. 1992; 298: 452–457.CrossrefMedlineGoogle Scholar23 Hurst JK, Lymar SV. Cellularly generated inorganic oxidants as natural microbicidal agents. Acc Chem Res. 1999; 32: 520–528.CrossrefGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Sabadashka M, Nagalievska M and Sybirna N (2020) Tyrosine nitration as a key event of signal transduction that regulates functional state of the cell, Cell Biology International, 10.1002/cbin.11301, 45:3, (481-497), Online publication date: 1-Mar-2021. Bayraktar A, Erbaş D, Akarca Dizakar S, Göktaş T, Ömeroğlu S and Öz Oyar E (2019) The Effect of Hepcidin on Cardiac Ischemia-Reperfusion Injury, Journal of Investigative Surgery, 10.1080/08941939.2019.1579275, 33:9, (813-821), Online publication date: 20-Oct-2020. Xu X, Wang B, Ren C, Hu J, Greenberg D, Chen T, Xie L and Jin K (2017) Recent Progress in Vascular Aging: Mechanisms and Its Role in Age-related Diseases, Aging and disease, 10.14336/AD.2017.0507, 8:4, (486), . Goud P, Goud A, Joshi N, Puscheck E, Diamond M and Abu-Soud H (2014) Dynamics of nitric oxide, altered follicular microenvironment, and oocyte quality in women with endometriosis, Fertility and Sterility, 10.1016/j.fertnstert.2014.03.053, 102:1, (151-159.e5), Online publication date: 1-Jul-2014. Rabbani Z, Mi J, Zhang Y, Delong M, Jackson I, Fleckenstein K, Salahuddin F, Zhang X, Clary B, Anscher M and Vujaskovic Z (2010) Hypoxia Inducible Factor 1α Signaling in Fractionated Radiation-Induced Lung Injury: Role of Oxidative Stress and Tissue Hypoxia, Radiation Research, 10.1667/RR1816.1, 173:2, (165-174), Online publication date: 1-Feb-2010. Mushlin P and Gelman S (2010) Hepatic Physiology and Pathophysiology Miller's Anesthesia, 10.1016/B978-0-443-06959-8.00017-0, (411-440), . Parihar A, Parihar M, Milner S and Bhat S (2008) Oxidative stress and anti-oxidative mobilization in burn injury, Burns, 10.1016/j.burns.2007.04.009, 34:1, (6-17), Online publication date: 1-Feb-2008. Rabbani Z, Salahuddin F, Yarmolenko P, Batinic-Haberle I, Thrasher B, Gauter-Fleckenstein B, Dewhirst M, Anscher M and Vujaskovic Z (2009) Low molecular weight catalytic metalloporphyrin antioxidant AEOL 10150 protects lungs from fractionated radiation, Free Radical Research, 10.1080/10715760701689550, 41:11, (1273-1282), Online publication date: 1-Jan-2007. Rae C, Cherry J, Land F and Land S (2006) Endotoxin-induced nitric oxide production rescues airway growth and maturation in atrophic fetal rat lung explants, Biochemical and Biophysical Research Communications, 10.1016/j.bbrc.2006.08.067, 349:1, (416-425), Online publication date: 1-Oct-2006. Qu L, Yang T, Yuan Y, Zhong P and Li Y (2006) Protein nitration increased by simulated weightlessness and decreased by melatonin and quercetin in PC12 cells, Nitric Oxide, 10.1016/j.niox.2005.12.006, 15:1, (58-63), Online publication date: 1-Aug-2006. Beaudeux J, Delattre J, Therond P, Bonnefont-Rousselot D, Legrand A and Peynet J (2006) Le stress oxydant, composante physiopathologique de l'athérosclérose, Immuno-analyse & Biologie Spécialisée, 10.1016/j.immbio.2006.02.001, 21:3, (144-150), Online publication date: 1-Jun-2006. Brzezinska A, Lohr N and Chilian W (2005) Electrophysiological effects of O 2 − · on the plasma membrane in vascular endothelial cells , American Journal of Physiology-Heart and Circulatory Physiology, 10.1152/ajpheart.00132.2005, 289:6, (H2379-H2386), Online publication date: 1-Dec-2005. Michelakis E The Role of the NO Axis and its Therapeutic Implications in Pulmonary Arterial Hypertension The Role of Nitric Oxide in Heart Failure, 10.1007/1-4020-7960-5_19, (213-229) Münzel T, Feil R, Mülsch A, Lohmann S, Hofmann F and Walter U (2003) Physiology and Pathophysiology of Vascular Signaling Controlled by Cyclic Guanosine 3′,5′-Cyclic Monophosphate–Dependent Protein Kinase, Circulation, 108:18, (2172-2183), Online publication date: 4-Nov-2003. Cho H, Shin H, Shin Y, Lee J and Hong K (2003) Role of nitric oxide in the CBF autoregulation during acute stage after subarachnoid haemorrhage in rat pial artery, Fundamental and Clinical Pharmacology, 10.1046/j.1472-8206.2003.00185.x, 17:5, (563-573), Online publication date: 1-Oct-2003. Bodamyali T, Kanczler J, Millar T, Stevens C and Blake D (2003) Free Radicals in Rheumatoid Arthritis Redox-Genome Interactions in Health and Disease, 10.1201/9780203912874.ch26, Online publication date: 12-Sep-2003. Shin H, Lee J, Dae Kim C, Kim Y, Hong J and Hong K (2016) Prevention of Impairment of Cerebral Blood Flow Autoregulation during Acute Stage of Subarachnoid Hemorrhage by Gene Transfer of Cu/Zn SOD-1 to Cerebral Vessels, Journal of Cerebral Blood Flow & Metabolism, 10.1097/01.WCB.0000036561.60552.63, 23:1, (111-120), Online publication date: 1-Jan-2003. Shin H, Lee J, Kim C, Kim Y, Hong J and Hong K (2003) Prevention of Impairment of Cerebral Blood Flow Autoregulation During Acute Stage of Subarachnoid Hemorrhage by Gene Transfer of Cu/Zn SOD-1 to Cerebral Vessels, Journal of Cerebral Blood Flow & Metabolism, 10.1097/00004647-200301000-00011, (111-120), Online publication date: 1-Jan-2003. Predescu D, Predescu S and Malik A (2002) Transport of nitrated albumin across continuous vascular endothelium, Proceedings of the National Academy of Sciences, 10.1073/pnas.212253499, 99:21, (13932-13937), Online publication date: 15-Oct-2002. Zaragoza C and Lamas S (2002) Endothelial Changes in Hypertension Cardiovascular Genomics: New Pathophysiological Concepts, 10.1007/978-1-4615-1005-5_9, (83-94), . August 17, 2001Vol 89, Issue 4 Advertisement Article InformationMetrics https://doi.org/10.1161/res.89.4.295PMID: 11509444 Originally publishedApril 3, 2018 Keywordssuperoxidenitrotyrosineprostacyclinpulmonary hypertensionPDF download Advertisement
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