Skip to main content
SpringerLink
Log in

Nitrite mediates cytoprotection after ischemia/reperfusion by modulating mitochondrial function

  • Review
  • Published:
Basic Research in Cardiology Aims and scope Submit manuscript

Abstract

Nitrite, once thought to be an inert biomarker of NO formation, is now recognized as an endocrine storage pool of bioactive NO. While nitrite mediates a number of hypoxic responses, one of its most robust effects is its ability to confer cytoprotection after ischemia/reperfusion in a number of organs and models. The mechanism of this cytoprotection appears to be mediated at the level of the mitochondrion. Here we review the studies demonstrating that nitrite is cytoprotective in the heart and describe the mechanism of this cytoprotection, which involves the post-translational modification of complex I leading to the modulation of mitochondrial reactive oxygen species generation at reperfusion. The mechanism of nitrite-dependent cytoprotection will be compared to other cytoprotective agents including NO and ischemic preconditioning.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Baker JE, Su J, Fu X, Hsu A, Gross GJ, Tweddell JS, Hogg N (2007) Nitrite confers protection against myocardial infarction: role of xanthine oxidoreductase, NADPH oxidase and K(ATP) channels. J Mol Cell Cardiol 43:437–444

    Article  PubMed  CAS  Google Scholar 

  2. Basireddy M, Isbell TS, Teng X, Patel RP, Agarwal A (2006) Effects of sodium nitrite on ischemia-reperfusion injury in the rat kidney. Am J Physiol Renal Physiol 290:F779–F786

    Article  PubMed  CAS  Google Scholar 

  3. Baxter GF, Ferdinandy P (2001) Delayed preconditioning of myocardium: current perspectives. Basic Res Cardiol 96:329–344

    Article  PubMed  CAS  Google Scholar 

  4. Bolli R (2001) Cardioprotective function of inducible nitric oxide synthase and role of nitric oxide in myocardial ischemia and preconditioning: an overview of a decade of research. J Mol Cell Cardiol 33:1897–1918

    Article  PubMed  CAS  Google Scholar 

  5. Bolli R, Dawn B, Tang XL, Qiu Y, Ping P, Xuan YT, Jones WK, Takano H, Guo Y, Zhang J (1998) The nitric oxide hypothesis of late preconditioning. Basic Res Cardiol 93:325–338

    Article  PubMed  CAS  Google Scholar 

  6. Borutaite V, Brown GC (2006) S-nitrosothiol inhibition of mitochondrial complex I causes a reversible increase in mitochondrial hydrogen peroxide production. Biochim Biophys Acta 1757:562–566

    Article  PubMed  CAS  Google Scholar 

  7. Bryan NS, Calvert JW, Elrod JW, Gundewar S, Ji SY, Lefer DJ (2007) Dietary nitrite supplementation protects against myocardial ischemia-reperfusion injury. Proc Natl Acad Sci USA 104:19144–19149

    Article  PubMed  CAS  Google Scholar 

  8. Bryan NS, Calvert JW, Gundewar S, Lefer DJ (2008) Dietary nitrite restores NO homeostasis and is cardioprotective in endothelial nitric oxide synthase-deficient mice. Free Radic Biol Med 45:468–474

    Article  PubMed  CAS  Google Scholar 

  9. Bryan NS, Fernandez BO, Bauer SM, Garcia-Saura MF, Milsom AB, Rassaf T, Maloney RE, Bharti A, Rodriguez J, Feelisch M (2005) Nitrite is a signaling molecule and regulator of gene expression in mammalian tissues. Nat Chem Biol 1:290–297

    Article  PubMed  CAS  Google Scholar 

  10. Burwell LS, Nadtochiy SM, Tompkins AJ, Young S, Brookes PS (2006) Direct evidence for S-nitrosation of mitochondrial complex I. Biochem J 394:627–634

    Article  PubMed  CAS  Google Scholar 

  11. Castello PR, David PS, McClure T, Crook Z, Poyton RO (2006) Mitochondrial cytochrome oxidase produces nitric oxide under hypoxic conditions: implications for oxygen sensing and hypoxic signaling in eukaryotes. Cell Metab 3:277–287

    Article  PubMed  CAS  Google Scholar 

  12. Chen Q, Camara AK, Stowe DF, Hoppel CL, Lesnefsky EJ (2007) Modulation of electron transport protects cardiac mitochondria and decreases myocardial injury during ischemia and reperfusion. Am J Physiol Cell Physiol 292:C137–C147

    Article  PubMed  CAS  Google Scholar 

  13. Chen Q, Moghaddas S, Hoppel CL, Lesnefsky EJ (2006) Reversible blockade of electron transport during ischemia protects mitochondria and decreases myocardial injury following reperfusion. J Pharmacol Exp Ther 319:1405–1412

    Article  PubMed  CAS  Google Scholar 

  14. Cosby K, Partovi KS, Crawford JH, Patel RP, Reiter CD, Martyr S, Yang BK, Waclawiw MA, Zalos G, Xu X, Huang KT, Shields H, Kim-Shapiro DB, Schechter AN, Cannon RO 3rd, Gladwin MT (2003) Nitrite reduction to nitric oxide by deoxyhemoglobin vasodilates the human circulation. Nat Med 9:1498–1505

    Article  PubMed  CAS  Google Scholar 

  15. Crawford JH, Isbell TS, Huang Z, Shiva S, Chacko BK, Schechter AN, Darley-Usmar VM, Kerby JD, Lang JD Jr, Kraus D, Ho C, Gladwin MT, Patel RP (2006) Hypoxia, red blood cells, and nitrite regulate NO-dependent hypoxic vasodilation. Blood 107:566–574

    Article  PubMed  CAS  Google Scholar 

  16. Dahm CC, Moore K, Murphy MP (2006) Persistent S-nitrosation of complex I and other mitochondrial membrane proteins by S-nitrosothiols but not nitric oxide or peroxynitrite: implications for the interaction of nitric oxide with mitochondria. J Biol Chem 281:10056–10065

    Article  PubMed  CAS  Google Scholar 

  17. Dawn B, Bolli R (2002) Role of nitric oxide in myocardial preconditioning. Ann N Y Acad Sci 962:18–41

    Article  PubMed  CAS  Google Scholar 

  18. Dejam A, Hunter CJ, Pelletier MM, Hsu LL, Machado RF, Shiva S, Power GG, Kelm M, Gladwin MT, Schechter AN (2005) Erythrocytes are the major intravascular storage sites of nitrite in human blood. Blood 106:734–739

    Article  PubMed  CAS  Google Scholar 

  19. Dezfulian C, Raat N, Shiva S, Gladwin MT (2007) Role of the anion nitrite in ischemia-reperfusion cytoprotection and therapeutics. Cardiovasc Res 75:327–338

    Article  PubMed  CAS  Google Scholar 

  20. Duranski MR, Greer JJ, Dejam A, Jaganmohan S, Hogg N, Langston W, Patel RP, Yet SF, Wang X, Kevil CG, Gladwin MT, Lefer DJ (2005) Cytoprotective effects of nitrite during in vivo ischemia-reperfusion of the heart and liver. J Clin Invest 115:1232–1240

    PubMed  CAS  Google Scholar 

  21. Duranski MR, Greer JJ, Dejam A, Jaganmohan S, Hogg N, Langston W, Patel RP, Yet SF, Wang X, Kevil CG, Gladwin MT, Lefer DJ (2005) Cytoprotective effects of nitrite during in vivo ischemia-reperfusion of the heart and liver. J Clin Invest 115:1232–1240

    PubMed  CAS  Google Scholar 

  22. Dweik RA, Guo FH, Uetani K, Erzurum SC (1997) Nitric oxide synthase in the human airway epithelium. Zhongguo Yao Li Xue Bao 18:550–552

    PubMed  CAS  Google Scholar 

  23. Feelisch M, Fernandez BO, Bryan NS, Garcia-Saura MF, Bauer S, Whitlock DR, Ford PC, Janero DR, Rodriguez J, Ashrafian H (2008) Tissue processing of nitrite in hypoxia: an intricate interplay of nitric oxide-generating and -scavenging systems. J Biol Chem 283:33927–33934

    Article  PubMed  CAS  Google Scholar 

  24. Galkin A, Moncada S (2007) S-nitrosation of mitochondrial complex I depends on its structural conformation. J Biol Chem 282:37448–37453

    Article  PubMed  CAS  Google Scholar 

  25. Gladwin MT, Schechter AN, Kim-Shapiro DB, Patel RP, Hogg N, Shiva S, Cannon RO 3rd, Kelm M, Wink DA, Espey MG, Oldfield EH, Pluta RM, Freeman BA, Lancaster JR Jr, Feelisch M, Lundberg JO (2005) The emerging biology of the nitrite anion. Nat Chem Biol 1:308–314

    Article  PubMed  CAS  Google Scholar 

  26. Gonzalez FM, Shiva S, Vincent PS, Ringwood LA, Hsu LY, Hon YY, Aletras AH, Cannon RO 3rd, Gladwin MT, Arai AE (2008) Nitrite anion provides potent cytoprotective and antiapoptotic effects as adjunctive therapy to reperfusion for acute myocardial infarction. Circulation 117:2986–2994

    Article  PubMed  CAS  Google Scholar 

  27. Guo Y, Li Q, Wu WJ, Tan W, Zhu X, Mu J, Bolli R (2008) Endothelial nitric oxide synthase is not necessary for the early phase of ischemic preconditioning in the mouse. J Mol Cell Cardiol 44:496–501

    Article  PubMed  CAS  Google Scholar 

  28. Hausenloy DJ, Yellon DM (2008) Clinical translation of cardioprotective strategies: report and recommendations of the Hatter Institute 5th international workshop on cardioprotection. Basic Res Cardiol 103:493–500

    Article  PubMed  Google Scholar 

  29. 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 (2008) Nitrite reductase activity of myoglobin regulates respiration and cellular viability in myocardial ischemia-reperfusion injury. Proc Natl Acad Sci USA 105:10256–10261

    Article  PubMed  CAS  Google Scholar 

  30. Honda HM, Korge P, Weiss JN (2005) Mitochondria and ischemia/reperfusion injury. Ann N Y Acad Sci 1047:248–258

    Article  PubMed  CAS  Google Scholar 

  31. Huang Z, Shiva S, Kim-Shapiro DB, Patel RP, Ringwood LA, Irby CE, Huang KT, Ho C, Hogg N, Schechter AN, Gladwin MT (2005) Enzymatic function of hemoglobin as a nitrite reductase that produces NO under allosteric control. J Clin Invest 115:2099–2107

    Article  PubMed  CAS  Google Scholar 

  32. Jones SP, Bolli R (2006) The ubiquitous role of nitric oxide in cardioprotection. J Mol Cell Cardiol 40:16–23

    Article  PubMed  CAS  Google Scholar 

  33. Jung KH, Chu K, Ko SY, Lee ST, Sinn DI, Park DK, Kim JM, Song EC, Kim M, Roh JK (2006) Early intravenous infusion of sodium nitrite protects brain against in vivo ischemia-reperfusion injury. Stroke 37:2744–2750

    Article  PubMed  CAS  Google Scholar 

  34. Kozlov AV, Staniek K, Nohl H (1999) Nitrite reductase activity is a novel function of mammalian mitochondria. FEBS Lett 454:127–130

    Article  PubMed  CAS  Google Scholar 

  35. Krieg T, Cohen MV, Downey JM (2003) Mitochondria and their role in preconditioning’s trigger phase. Basic Res Cardiol 98:228–234

    PubMed  CAS  Google Scholar 

  36. Kumar D, Branch BG, Pattillo CB, Hood J, Thoma S, Simpson S, Illum S, Arora N, Chidlow JH Jr, Langston W, Teng X, Lefer DJ, Patel RP, Kevil CG (2008) Chronic sodium nitrite therapy augments ischemia-induced angiogenesis and arteriogenesis. Proc Natl Acad Sci USA 105:7540–7545

    Article  PubMed  CAS  Google Scholar 

  37. Lu P, Liu F, Yao Z, Wang CY, Chen DD, Tian Y, Zhang JH, Wu YH (2005) Nitrite-derived nitric oxide by xanthine oxidoreductase protects the liver against ischemia-reperfusion injury. Hepatobiliary Pancreat Dis Int 4:350–355

    PubMed  CAS  Google Scholar 

  38. Lundberg JO, Weitzberg E, Gladwin MT (2008) The nitrate-nitrite-nitric oxide pathway in physiology and therapeutics. Nat Rev Drug Discov 7:156–167

    Article  PubMed  CAS  Google Scholar 

  39. Martin C, Schulz R, Post H, Boengler K, Kelm M, Kleinbongard P, Gres P, Skyschally A, Konietzka I, Heusch G (2007) Microdialysis-based analysis of interstitial NO in situ: NO synthase-independent NO formation during myocardial ischemia. Cardiovasc Res 74:46–55

    Article  PubMed  CAS  Google Scholar 

  40. Miura T, Miki T (2008) Limitation of myocardial infarct size in the clinical setting: current status and challenges in translating animal experiments into clinical therapy. Basic Res Cardiol 103:501–513

    Article  PubMed  Google Scholar 

  41. Nadtochiy SM, Baker PR, Freeman BA, Brookes PS (2008) Mitochondrial nitroalkene formation and mild uncoupling in ischaemic preconditioning: implications for cardioprotection. Cardiovasc Res (in press)

  42. Nadtochiy SM, Burwell LS, Brookes PS (2007) Cardioprotection and mitochondrial S-nitrosation: effects of S-nitroso-2-mercaptopropionyl glycine (SNO-MPG) in cardiac ischemia-reperfusion injury. J Mol Cell Cardiol 42:812–825

    Article  PubMed  CAS  Google Scholar 

  43. Patel VC, Yellon DM, Singh KJ, Neild GH, Woolfson RG (1993) Inhibition of nitric oxide limits infarct size in the in situ rabbit heart. Biochem Biophys Res Commun 194:234–238

    Article  PubMed  CAS  Google Scholar 

  44. Post H, Schulz R, Behrends M, Gres P, Umschlag C, Heusch G (2000) No involvement of endogenous nitric oxide in classical ischemic preconditioning in swine. J Mol Cell Cardiol 32:725–733

    Article  PubMed  CAS  Google Scholar 

  45. Rassaf T, Flogel U, Drexhage C, Hendgen-Cotta U, Kelm M, Schrader J (2007) Nitrite reductase function of deoxymyoglobin: oxygen sensor and regulator of cardiac energetics and function. Circ Res 100:1749–1754

    Article  PubMed  CAS  Google Scholar 

  46. Reimer KA, Jennings RB (1996) Ischemic preconditioning: a brief review. Basic Res Cardiol 91:1–4

    Article  PubMed  CAS  Google Scholar 

  47. Rodriguez J, Maloney RE, Rassaf T, Bryan NS, Feelisch M (2003) Chemical nature of nitric oxide storage forms in rat vascular tissue. Proc Natl Acad Sci USA 100:336–341

    Article  PubMed  CAS  Google Scholar 

  48. Rouslin W (1983) Mitochondrial complexes I, II, III, IV, and V in myocardial ischemia and autolysis. Am J Physiol 244:H743–H748

    PubMed  CAS  Google Scholar 

  49. Sack MN (2006) Mitochondrial depolarization and the role of uncoupling proteins in ischemia tolerance. Cardiovasc Res 72:210–219

    Article  PubMed  CAS  Google Scholar 

  50. Sharp BR, Jones SP, Rimmer DM, Lefer DJ (2002) Differential response to myocardial reperfusion injury in eNOS-deficient mice. Am J Physiol Heart Circ Physiol 282:H2422–H2426

    PubMed  CAS  Google Scholar 

  51. Shiva S, Huang Z, Grubina R, Sun J, Ringwood LA, MacArthur PH, Xu X, Murphy E, Darley-Usmar VM, Gladwin MT (2007) Deoxymyoglobin is a nitrite reductase that generates nitric oxide and regulates mitochondrial respiration. Circ Res 100:654–661

    Article  PubMed  CAS  Google Scholar 

  52. 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 (2007) Nitrite augments tolerance to ischemia/reperfusion injury via the modulation of mitochondrial electron transfer. J Exp Med 204:2089–2102

    Article  PubMed  CAS  Google Scholar 

  53. Shiva S, Wang X, Ringwood LA, Xu X, Yuditskaya S, Annavajjhala V, Miyajima H, Hogg N, Harris ZL, Gladwin MT (2006) Ceruloplasmin is a NO oxidase and nitrite synthase that determines endocrine NO homeostasis. Nat Chem Biol 2:486–493

    Article  PubMed  CAS  Google Scholar 

  54. Sumeray MS, Rees DD, Yellon DM (2000) Infarct size and nitric oxide synthase in murine myocardium. J Mol Cell Cardiol 32:35–42

    Article  PubMed  CAS  Google Scholar 

  55. Tripatara P, Patel NS, Webb A, Rathod K, Lecomte FM, Mazzon E, Cuzzocrea S, Yaqoob MM, Ahluwalia A, Thiemermann C (2007) Nitrite-derived nitric oxide protects the rat kidney against ischemia/reperfusion injury in vivo: role for xanthine oxidoreductase. J Am Soc Nephrol 18:570–580

    Article  PubMed  CAS  Google Scholar 

  56. Webb A, Bond R, McLean P, Uppal R, Benjamin N, Ahluwalia A (2004) Reduction of nitrite to nitric oxide during ischemia protects against myocardial ischemia-reperfusion damage. Proc Natl Acad Sci USA 101:13683–13688

    Article  PubMed  CAS  Google Scholar 

  57. Webb A, Bond R, McLean P, Uppal R, Benjamin N, Ahluwalia A (2004) Reduction of nitrite to nitric oxide during ischemia protects against myocardial ischemia-reperfusion damage. Proc Natl Acad Sci USA 101:13683–13688

    Article  PubMed  CAS  Google Scholar 

  58. Webb AJ, Patel N, Loukogeorgakis S, Okorie M, Aboud Z, Misra S, Rashid R, Miall P, Deanfield J, Benjamin N, MacAllister R, Hobbs AJ, Ahluwalia A (2008) Acute blood pressure lowering, vasoprotective, and antiplatelet properties of dietary nitrate via bioconversion to nitrite. Hypertension 51:784–790

    Article  PubMed  CAS  Google Scholar 

  59. Yellon DM, Downey JM (2003) Preconditioning the myocardium: from cellular physiology to clinical cardiology. Physiol Rev 83:1113–1151

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, USA

    Sruti Shiva

  2. Hemostasis and Vascular Biology Research Institute, University of Pittsburgh, Room 7018, BST III, 3501 5th Avenue, Pittsburgh, PA, 15260, USA

    Sruti Shiva & Mark T. Gladwin

  3. Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, 15260, USA

    Mark T. Gladwin

Authors
  1. Sruti Shiva
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mark T. Gladwin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sruti Shiva.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Shiva, S., Gladwin, M.T. Nitrite mediates cytoprotection after ischemia/reperfusion by modulating mitochondrial function. Basic Res Cardiol 104, 113–119 (2009). https://doi.org/10.1007/s00395-009-0009-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00395-009-0009-3

Keywords

Search

Navigation