Is Nitrite the Circulating Endocrine Effector of Remote Ischemic Preconditioning?
2014; Lippincott Williams & Wilkins; Volume: 114; Issue: 10 Linguagem: Inglês
10.1161/circresaha.114.303960
ISSN1524-4571
Autores Tópico(s)Cardiac Arrest and Resuscitation
ResumoHomeCirculation ResearchVol. 114, No. 10Is Nitrite the Circulating Endocrine Effector of Remote Ischemic Preconditioning? Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBIs Nitrite the Circulating Endocrine Effector of Remote Ischemic Preconditioning? Paola Corti and Mark T. Gladwin Paola CortiPaola Corti From the Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, Department of Medicine (P.C., M.T.G.) and Department of Pulmonary, Allergy and Critical Care Medicine (M.T.G.), University of Pittsburgh, PA. and Mark T. GladwinMark T. Gladwin From the Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, Department of Medicine (P.C., M.T.G.) and Department of Pulmonary, Allergy and Critical Care Medicine (M.T.G.), University of Pittsburgh, PA. Originally published9 May 2014https://doi.org/10.1161/CIRCRESAHA.114.303960Circulation Research. 2014;114:1554–1557Nitric Oxide SignalingNitric oxide (NO) is a highly diffusible, free radical signaling molecule that is produced by the endothelial NO synthase (eNOS) enzyme, which converts l-arginine and molecular oxygen into l-citrulline and NO.1,2 NO diffuses from the endothelium to the smooth muscle where it binds with high affinity to the heme group of soluble guanylate cyclase, which in turn catalyzes the conversion of GTP to cGMP.3 NO signaling is largely paracrine, with potential endocrine effects limited by its radical nature and extremely high reactivity with other heme-containing proteins such as hemoglobin and myoglobin.4 When NO encounters oxyhemoglobin in blood or oxymyoglobin in cardiomyocytes, it reacts at rates near the diffusion limit to form nitrate and methemoglobin (dioxygenation reaction).5,6 It will also react with the deoxyhemes of these proteins to form iron–nitrosyl complexes, which can release NO but inefficiently via the oxidative denitrosylation reaction.7 These 2 reactions, dioxygenation and iron nitrosylation, prevent NO from forming in the endothelium and diffusing to distant organ targets, such as the heart, intestine, kidney, brain, or liver.Article, see p 1601Despite the strict paracrine limitations imposed by this chemistry, several studies suggested that endocrine NO signaling is possible. The Kubes' group showed that NO delivered by inhalation to cats could improve blood flow and limit inflammation in the cat intestine subjected to ischemia–reperfusion (I/R) injury8; Cannon et al6 later showed that this was possible in the human circulation. Many subsequent studies have shown that inhaled NO could rescue distal organs from I/R injury and infarction. In fact, upregulation of eNOS selectively in the heart could rescue the liver from I/R injury.9 However, free NO cannot account for these effects based on the short half-life of NO in blood, on the order of ≤2 milliseconds.10Many investigators have examined reaction products of NO in blood, attempting to determine the mediator of endocrine NO signaling. Although S-nitroso-albumin and S-nitrosohemoglobin were first proposed as endocrine NO metabolites, the levels of these species even during NO inhalation are low, using validated chemiluminescent detection methods.4 Human studies with NO inhalation suggested that the NO oxidation product nitrite (NO2−) increases significantly, with arterial levels higher than venous levels, suggesting this anion could account for the effect.4,6,11 Unlike authentic NO, nitrite has a half-life in mammals approaching 60 minutes.12 Infusions of nitrite in humans and animal models indicated that nitrite was a potent vasodilator and cytoprotective agent that could mimic all the observed effects of NO inhalation.13–16 Recent studies have carefully repleted nitrite levels to those observed with NO inhalation and produced similar reductions in organ infarction volumes, confirming the role of nitrite as the endocrine effector of inhaled NO.17Elusive Endocrine Mediator of Remote Ischemic PreconditioningAnother line of investigation suggests the existence of an endocrine mediator of organ cytoprotection during remote ischemic preconditioning (rIPC). The idea that a signal transduction exists between the local site of remote ischemia and the myocardium was demonstrated by Przyklenk et al18 in the early 1990s. They found, using a canine model, that brief episodes of ischemia and reperfusion in the circumflex coronary artery reduce the size of the myocardial infarct arising from the occlusion of the left anterior descending artery.18 This form of myocardial protection was subsequently found to occur with remote ischemia and reperfusion of noncardiac organs. Transient ischemia of a variety of tissues such as kidney, small bowel, liver, skeletal muscle, and even brain induces a systemic protective effect against the subsequent extended I/R injury of the myocardium.19–21 Such phenomenon was termed "preconditioning at a distance"22 and seems to be highly conserved across species. Animal studies with transplanted hearts further support the role of a circulating substance or a group of transduction mediators with protective effects against I/R injury. Remote limb preconditioning of a pig that received a donor heart was able to reduce myocardial infarct size,23 and hearts excised from a rat that had been subjected to remote limb preconditioning experienced a smaller infarct size when subjected to sustained I/R on a Langendorff apparatus.24The finding that a reperfusion period of the remote preconditioned organ is required after the brief ischemia suggests that the reperfusion period may be needed to wash out a humoral factor generated by the preconditioning ischemia, which is then transported to the heart.21 Many experimental studies have attempted to identify the nature of the endocrine mediators circulating in the blood stream, which conveys the preconditioning signal from the remote organ to the heart.25–27 However, the actual identity of the humoral mediator remains unknown.NO and CardioprotectionThere is a large body of literature describing the protective properties of NO as an element of the cytoprotective factor, despite the limitations of endocrine movement to a remote site. Endogenous NOS-derived NO seems to play a pivotal role in mediating the protective effect of hindlimb rIPC in reducing liver damage, and this is abrogated by treatments with the NO scavenger carboxy-2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (cPTIO) and inhibited in the eNOS knockout mouse.28 Tokuno et al20 have implicated inducible NOS activation as a trigger for delayed rIPC of the heart using cerebral ischemia as preconditioning stimulus. The cardioprotective effect was seen 24 hours later and was absent in inducible NOS knockout mice. Further studies demonstrated that NO is necessary for the development of ischemia-induced delayed protection against both myocardial stunning and myocardial infarction.29 Although it is clear that NO synthase and NO seem to participate in the process of rIPC, the mechanism for NO transport to a distant site in this process and the nature of the endocrine rIPC mediator have remained a mystery.Nitrite as Endocrine Mediator of rIPCIn this issue of Circulation Research, Rassaf et al30 investigate the mechanism of rIPC and explore the possible identity of the circulating endocrine mediator. They first find in human studies that, similar to the case with inhaled NO exposure, the levels of plasma nitrite increase after shear-mediated eNOS activation during brachial artery occlusion and release (reactive hyperemia). This is caused by eNOS activation with NO formation and oxidation to the more stable nitrite. They confirm this by blocking the high-flow shear associated with reactive hyperemia by using partial 50% compression of the brachial artery after ischemia. This is a creative control, allowing for regional ischemia without the shear-induced activation of eNOS and formation of intravascular nitrite.They then do rIPC studies in the legs of mice and show that nitrite levels increase. Inhibition of NO with cPTIO or in eNOS knockout mice prevents the rise in nitrite and rIPC effects on myocardial infarction. This association is mechanistically confirmed by infusions of nitrite to match elevated levels observed with rIPC. Finally, they infuse human plasma with and without rIPC into the isolated heart model of I/R and show that elevations in nitrite (removed with acidified sulfanilamide and repleted) account for effects. Overall, the studies are highly translational and use creative methodologies to test a major pathway in biology, the process, and effector of rIPC.Myoglobin as Nitrite ReductaseAlthough these studies suggest that nitrite forms during rIPC and travels in the plasma to the heart, how is it then converted in the heart back into cytoprotective NO? During ischemia, nitrite is reduced to NO and N2O3 by different nitrite reductase enzyme systems.31,32 Mitochondrial NO and S-nitrosothiols formed from nitrite dynamically and reversibly inhibit complex I during reperfusion, which limits reactive oxygen species formation from complexes I and III.33,34 This ultimately prevents the opening of the mitochondrial permeability transition pore and the release of cytochrome c. It has recently been shown that the site of nitrosation is on cysteine 39 of the ND3 (NADH dehydrogenase, subunit 3) subunit of complex I.34 Several enzymes are required to convert nitrite into NO during organ ischemia. For example, in the heart, deoxygenated myoglobin acts as a functional nitrite reductase35 (Figure). Nitrite-dependent NO formation is significantly decreased in myoglobin-deficient hearts,37 and nitrite administration reduces myocardial infarction with abrogated effects in the myoglobin knockout mice.38 In the current study, Rassaf et al30 show that the effect of rIPC is inhibited in the myoglobin knockout mouse, providing additional support that the endocrine mediator of this effect is nitrite, which is produced in the extremity and travels in blood to the heart, where it is reduced by myoglobin to produce NO.Download figureDownload PowerPointFigure. Mechanisms of nitrite-mediated cytoprotection. In the cardiomyocytes, nitrite is reduced to nitric oxide (NO) by reactions with deoxymyoglobin and then can react with and inhibit complex I of the mitochondrial electron transport chain. This inhibition is reversible and occurs immediately during reperfusion to limit reactive oxygen species (ROS) formation and to prevent the release of cytochrome c. Adapted from Bueno et al36 (Mary Ann Liebert, Inc, 2013). SNO indicates S-nitrosation of complex I.ConclusionsA potential limitation of the current study is the reliance on mouse models of myocardial infarction to test the cytoprotective effects of nitrite. A recent clinical trial presented at the 2013 American Heart Association meeting investigating the therapeutic effects of nitrite in ST-segment–elevation myocardial infarction showed that sodium nitrite administered before reperfusion does not reduce infarct size.39 Evaluation of the full results of this trial will be required to understand the dose, timing, plasma nitrite levels achieved, and fidelity of the study design. However, these results are likely to raise questions about the relevance of findings from mouse models of I/R injury to human disease.In summary, this study provides compelling evidence that limb ischemia causes metabolic vasodilation that leads to increased blood flow and shear force on the endothelium of conductance blood vessels to activate eNOS. Activated eNOS produces NO, which is oxidized in plasma to nitrite. Nitrite then circulates as the endocrine mediator of rIPC and travels to the heart. Finally, when the heart is subjected to ischemia, the nitrite is then reduced by deoxymyoglobin to form NO in the cardiomyocyte, limiting cellular injury and infarction.Sources of FundingM.T. Gladwin receives research support from National Institutes of Health grants RO1HL098032, RO1HL096973, P01HL103455, and T32 HL110849 and the Institute for Transfusion Medicine and Hemophilia Center of Western Pennsylvania. P. Corti is supported by a fellowship from the Ri.MED Foundation.DisclosuresM.T. Gladwin is listed as coinventor on a National Institutes of Health government patent for the use of nitrite salts in cardiovascular diseases. M.T. Gladwin consults with Aires Pharmaceuticals on the development of a phase II proof-of-concept trial using inhaled nitrite for pulmonary arterial hypertension. P. Corti reports no conflicts.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Correspondence to Mark T. Gladwin, MD, Vascular Medicine Institute, University of Pittsburgh, NW 628 Montefiore Hospital, 3459 Fifth Ave, Pittsburgh, PA 15213. E-mail [email protected]References1. Palmer RM, Ashton DS, Moncada S. Vascular endothelial cells synthesize nitric oxide from L-arginine.Nature. 1988; 333:664–666.CrossrefMedlineGoogle Scholar2. Palmer RM, Ferrige AG, Moncada S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor.Nature. 1987; 327:524–526.CrossrefMedlineGoogle Scholar3. Gladwin MT. Deconstructing endothelial dysfunction: soluble guanylyl cyclase oxidation and the NO resistance syndrome.J Clin Invest. 2006; 116:2330–2332.CrossrefMedlineGoogle Scholar4. Gladwin MT, Ognibene FP, Pannell LK, Nichols JS, Pease-Fye ME, Shelhamer JH, Schechter AN. Relative role of heme nitrosylation and beta-cysteine 93 nitrosation in the transport and metabolism of nitric oxide by hemoglobin in the human circulation.Proc Natl Acad Sci U S A. 2000; 97:9943–9948.CrossrefMedlineGoogle Scholar5. Raat NJ, Tabima DM, Specht PA, Tejero J, Champion HC, Kim-Shapiro DB, Baust J, Mik EG, Hildesheim M, Stasch JP, Becker EM, Truebel H, Gladwin MT. Direct sGC activation bypasses NO scavenging reactions of intravascular free oxy-hemoglobin and limits vasoconstriction.Antioxid Redox Signal. 2013; 19:2232–2243.CrossrefMedlineGoogle Scholar6. Cannon RO, Schechter AN, Panza JA, Ognibene FP, Pease-Fye ME, Waclawiw MA, Shelhamer JH, Gladwin MT. Effects of inhaled nitric oxide on regional blood flow are consistent with intravascular nitric oxide delivery.J Clin Invest. 2001; 108:279–287.CrossrefMedlineGoogle Scholar7. Basu S, Grubina R, Huang J, et al. Catalytic generation of N2O3 by the concerted nitrite reductase and anhydrase activity of hemoglobin.Nat Chem Biol. 2007; 3:785–794.CrossrefMedlineGoogle Scholar8. Fox-Robichaud A, Payne D, Hasan SU, Ostrovsky L, Fairhead T, Reinhardt P, Kubes P. Inhaled NO as a viable antiadhesive therapy for ischemia/reperfusion injury of distal microvascular beds.J Clin Invest. 1998; 101:2497–2505.CrossrefMedlineGoogle Scholar9. Elrod JW, Calvert JW, Gundewar S, Bryan NS, Lefer DJ. Nitric oxide promotes distant organ protection: evidence for an endocrine role of nitric oxide.Proc Natl Acad Sci U S A. 2008; 105:11430–11435.CrossrefMedlineGoogle Scholar10. Liu X, Miller MJ, Joshi MS, Sadowska-Krowicka H, Clark DA, Lancaster JRDiffusion-limited reaction of free nitric oxide with erythrocytes.J Biol Chem. 1998; 273:18709–18713.CrossrefMedlineGoogle Scholar11. Gladwin MT, Shelhamer JH, Schechter AN, Pease-Fye ME, Waclawiw MA, Panza JA, Ognibene FP, Cannon RO. Role of circulating nitrite and S-nitrosohemoglobin in the regulation of regional blood flow in humans.Proc Natl Acad Sci U S A. 2000; 97:11482–11487.CrossrefMedlineGoogle Scholar12. Dejam A, Hunter CJ, Tremonti C, Pluta RM, Hon YY, Grimes G, Partovi K, Pelletier MM, Oldfield EH, Cannon RO, Schechter AN, Gladwin MT. Nitrite infusion in humans and nonhuman primates: endocrine effects, pharmacokinetics, and tolerance formation.Circulation. 2007; 116:1821–1831.LinkGoogle Scholar13. Cosby K, Partovi KS, Crawford JH, et al. Nitrite reduction to nitric oxide by deoxyhemoglobin vasodilates the human circulation.Nat Med. 2003; 9:1498–1505.CrossrefMedlineGoogle Scholar14. Webb A, Bond R, McLean P, Uppal R, Benjamin N, Ahluwalia A. Reduction of nitrite to nitric oxide during ischemia protects against myocardial ischemia-reperfusion damage.Proc Natl Acad Sci U S A. 2004; 101:13683–13688.CrossrefMedlineGoogle Scholar15. Duranski MR, Greer JJ, Dejam A, Jaganmohan S, Hogg N, Langston W, Patel RP, Yet SF, Wang X, Kevil CG, Gladwin MT, Lefer DJ. Cytoprotective effects of nitrite during in vivo ischemia-reperfusion of the heart and liver.J Clin Invest. 2005; 115:1232–1240.CrossrefMedlineGoogle Scholar16. Gonzalez FM, Shiva S, Vincent PS, Ringwood LA, Hsu LY, Hon YY, Aletras AH, Cannon RO, Gladwin MT, Arai AE. Nitrite anion provides potent cytoprotective and antiapoptotic effects as adjunctive therapy to reperfusion for acute myocardial infarction.Circulation. 2008; 117:2986–2994.LinkGoogle Scholar17. Neye N, Enigk F, Shiva S, Habazettl H, Plesnila N, Kuppe H, Gladwin MT, Kuebler WM. Inhalation of NO during myocardial ischemia reduces infarct size and improves cardiac function.Intensive Care Med. 2012; 38:1381–1391.CrossrefMedlineGoogle Scholar18. Przyklenk K, Bauer B, Ovize M, Kloner RA, Whittaker P. Regional ischemic 'preconditioning' protects remote virgin myocardium from subsequent sustained coronary occlusion.Circulation. 1993; 87:893–899.LinkGoogle Scholar19. Gho BC, Schoemaker RG, van den Doel MA, Duncker DJ, Verdouw PD. Myocardial protection by brief ischemia in noncardiac tissue.Circulation. 1996; 94:2193–2200.LinkGoogle Scholar20. Tokuno S, Hinokiyama K, Tokuno K, Löwbeer C, Hansson LO, Valen G. Spontaneous ischemic events in the brain and heart adapt the hearts of severely atherosclerotic mice to ischemia.Arterioscler Thromb Vasc Biol. 2002; 22:995–1001.LinkGoogle Scholar21. Hausenloy DJ, Yellon DM. Remote ischaemic preconditioning: underlying mechanisms and clinical application.Cardiovasc Res. 2008; 79:377–386.CrossrefMedlineGoogle Scholar22. Dickson EW, Porcaro WA, Fenton RA, Heard SO, Reindhardt CP, Renzi FP, Przyklenk K. "Preconditioning at a distance" in the isolated rabbit heart.Acad Emerg Med. 2000; 7:311–317.CrossrefMedlineGoogle Scholar23. Konstantinov IE, Li J, Cheung MM, Shimizu M, Stokoe J, Kharbanda RK, Redington AN. Remote ischemic preconditioning of the recipient reduces myocardial ischemia-reperfusion injury of the denervated donor heart via a Katp channel-dependent mechanism.Transplantation. 2005; 79:1691–1695.CrossrefMedlineGoogle Scholar24. Kristiansen SB, Henning O, Kharbanda RK, Nielsen-Kudsk JE, Schmidt MR, Redington AN, Nielsen TT, Bøtker HE. Remote preconditioning reduces ischemic injury in the explanted heart by a KATP channel-dependent mechanism.Am J Physiol Heart Circ Physiol. 2005; 288:H1252–H1256.CrossrefMedlineGoogle Scholar25. Lang SC, Elsässer A, Scheler C, Vetter S, Tiefenbacher CP, Kübler W, Katus HA, Vogt AM. Myocardial preconditioning and remote renal preconditioning–identifying a protective factor using proteomic methods?Basic Res Cardiol. 2006; 101:149–158.CrossrefMedlineGoogle Scholar26. Serejo FC, Rodrigues LF, da Silva Tavares KC, de Carvalho AC, Nascimento JH. Cardioprotective properties of humoral factors released from rat hearts subject to ischemic preconditioning.J Cardiovasc Pharmacol. 2007; 49:214–220.CrossrefMedlineGoogle Scholar27. Shimizu M, Tropak M, Diaz RJ, Suto F, Surendra H, Kuzmin E, Li J, Gross G, Wilson GJ, Callahan J, Redington AN. Transient limb ischaemia remotely preconditions through a humoral mechanism acting directly on the myocardium: evidence suggesting cross-species protection.Clin Sci (Lond). 2009; 117:191–200.CrossrefMedlineGoogle Scholar28. Abu-Amara M, Yang SY, Quaglia A, Rowley P, de Mel A, Tapuria N, Seifalian A, Davidson B, Fuller B. Nitric oxide is an essential mediator of the protective effects of remote ischaemic preconditioning in a mouse model of liver ischaemia/reperfusion injury.Clin Sci (Lond). 2011; 121:257–266.CrossrefMedlineGoogle Scholar29. Bolli R. The late phase of preconditioning.Circ Res. 2000; 87:972–983.LinkGoogle Scholar30. Rassaf T, Totzeck M, Hendgen-Cotta UB, Shiva S, Heusch G, Kelm M. Circulating nitrite contributes to cardioprotection by remote ischemic preconditioning.Circ Res. 2014;114:1601–1610.LinkGoogle Scholar31. Sparacino-Watkins CE, Tejero J, Sun B, Gauthier MC, Thomas J, Ragireddy V, Merchant BA, Wang J, Azarov I, Basu P, Gladwin MT. Nitrite reductase and nitric-oxide synthase activity of the mitochondrial molybdopterin enzymes mARC1 and mARC2.J Biol Chem. 2014; 289:10345–10358.CrossrefMedlineGoogle Scholar32. Tejero J, Gladwin MT. The globin superfamily: functions in nitric oxide formation and decay [published online ahead of print January 30, 2014].Biol Chem. doi: 10.1515/hsz-2013-0289. http://dx.doi.org/10.1515/hsz-2013-0289. Accessed April 25, 2014.Google Scholar33. Shiva S, Sack MN, Greer JJ, Duranski M, Ringwood LA, Burwell L, Wang X, MacArthur PH, Shoja A, Raghavachari N, Calvert JW, Brookes PS, Lefer DJ, Gladwin MT. Nitrite augments tolerance to ischemia/reperfusion injury via the modulation of mitochondrial electron transfer.J Exp Med. 2007; 204:2089–2102.CrossrefMedlineGoogle Scholar34. Chouchani ET, Methner C, Nadtochiy SM, et al. Cardioprotection by S-nitrosation of a cysteine switch on mitochondrial complex I.Nat Med. 2013; 19:753–759.CrossrefMedlineGoogle Scholar35. Shiva S, Huang Z, Grubina R, Sun J, Ringwood LA, MacArthur PH, Xu X, Murphy E, Darley-Usmar VM, Gladwin MT. Deoxymyoglobin is a nitrite reductase that generates nitric oxide and regulates mitochondrial respiration.Circ Res. 2007; 100:654–661.LinkGoogle Scholar36. Bueno M, Wang J, Mora AL, Gladwin MT. Nitrite signaling in pulmonary hypertension: mechanisms of bioactivation, signaling, and therapeutics.Antioxid Redox Signal. 2013; 18:1797–1809.CrossrefMedlineGoogle Scholar37. Rassaf T, Flögel U, Drexhage C, Hendgen-Cotta U, Kelm M, Schrader J. Nitrite reductase function of deoxymyoglobin: oxygen sensor and regulator of cardiac energetics and function.Circ Res. 2007; 100:1749–1754.LinkGoogle Scholar38. Hendgen-Cotta UB, Merx MW, Shiva S, Schmitz J, Becher S, Klare JP, Steinhoff HJ, Goedecke A, Schrader J, Gladwin MT, Kelm M, Rassaf T. Nitrite reductase activity of myoglobin regulates respiration and cellular viability in myocardial ischemia-reperfusion injury.Proc Natl Acad Sci U S A. 2008; 105:10256–10261.CrossrefMedlineGoogle Scholar39. Siddiqi N, Neil C, Bruce M, et al. Intravenous sodium nitrite in acute ST-elevation myocardial infarction: a randomized controlled trial (NIAMI) [published online ahead of print March 17, 2014].Eur Heart J. doi: 10.1093/eurheartj/ehu096. http://dx.doi.org/10.1093/eurheartj/ehu096. Accessed April 25, 2014.Google Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By García-de-la-Asunción J, Perez-Griera J, Moreno T, Duca A, García-del-Olmo N, Belda J and Soro M (2020) Limb Ischemic Conditioning Induces Oxidative Stress Followed by a Correlated Increase of HIF-1α in Healthy Volunteers, Annals of Vascular Surgery, 10.1016/j.avsg.2019.06.033, 62, (412-419), Online publication date: 1-Jan-2020. Parray A, Ma Y, Alam M, Akhtar N, Salam A, Mir F, Qadri S, Pananchikkal S, Priyanka R, Kamran S, Winship I and Shuaib A (2020) An increase in AMPK/e-NOS signaling and attenuation of MMP-9 may contribute to remote ischemic perconditioning associated neuroprotection in rat model of focal ischemia, Brain Research, 10.1016/j.brainres.2020.146860, 1740, (146860), Online publication date: 1-Aug-2020. Zhou D, Ding J, Ya J, Pan L, Wang Y, Ji X and Meng R (2018) Remote ischemic conditioning: a promising therapeutic intervention for multi-organ protection, Aging, 10.18632/aging.101527, 10:8, (1825-1855), Online publication date: 16-Aug-2018. Ormerod J, Evans J, Contractor H, Beretta M, Arif S, Fernandez B, Feelisch M, Mayer B, Kharbanda R, Frenneaux M and Ashrafian H (2017) Human Second Window Pre-Conditioning and Post-Conditioning by Nitrite Is Influenced by a Common Polymorphism in Mitochondrial Aldehyde Dehydrogenase, JACC: Basic to Translational Science, 10.1016/j.jacbts.2016.11.006, 2:1, (13-21), Online publication date: 1-Feb-2017. Yuan S and Kevil C (2016) Nitric Oxide and Hydrogen Sulfide Regulation of Ischemic Vascular Remodeling, Microcirculation, 10.1111/micc.12248, 23:2, (134-145), Online publication date: 1-Feb-2016. Gill R, Kuriakose R, Gertz Z, Salloum F, Xi L and Kukreja R (2015) Remote ischemic preconditioning for myocardial protection: update on mechanisms and clinical relevance, Molecular and Cellular Biochemistry, 10.1007/s11010-014-2312-z, 402:1-2, (41-49), Online publication date: 1-Apr-2015. Chai Q, Liu J and Hu Y (2014) Comparison of femoral and aortic remote ischaemia preconditioning for cardioprotection against myocardial ischaemia/reperfusion injury in a rat model, Interactive CardioVascular and Thoracic Surgery, 10.1093/icvts/ivu303, 19:6, (1013-1018), Online publication date: 1-Dec-2014. Benstoem C, Stoppe C, Liakopoulos O, Ney J, Hasenclever D, Meybohm P and Goetzenich A (2017) Remote ischaemic preconditioning for coronary artery bypass grafting (with or without valve surgery), Cochrane Database of Systematic Reviews, 10.1002/14651858.CD011719.pub3, 2017:5 Benstoem C, Stoppe C, Liakopoulos O, Meybohm P, Clayton T, Yellon D, Hausenloy D, Goetzenich A and Benstoem C (2015) Remote ischaemic preconditioning for coronary artery bypass grafting Cochrane Database of Systematic Reviews, 10.1002/14651858.CD011719 A Mohamed M (2015) NO2- Mediates the Heart Protection of Remote Ischemic Preconditioning, MOJ Clinical & Medical Case Reports, 10.15406/mojcr.2015.02.00024, 2:3 Benstoem C, Stoppe C, Liakopoulos O, Meybohm P, Clayton T, Yellon D, Hausenloy D, Goetzenich A and Benstoem C (2015) Remote ischaemic preconditioning for coronary artery bypass grafting Cochrane Database of Systematic Reviews, 10.1002/14651858.CD011719.pub2 May 9, 2014Vol 114, Issue 10 Advertisement Article InformationMetrics © 2014 American Heart Association, Inc.https://doi.org/10.1161/CIRCRESAHA.114.303960PMID: 24812347 Originally publishedMay 9, 2014 Keywordsnitritesischemic preconditioningEditorialsnitric oxidemyoglobinPDF download Advertisement SubjectsEndothelium/Vascular Type/Nitric Oxide
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