Skip to main content
SpringerLink
Log in

Part I: Pathogenetic Role of Peroxynitrite in the Development of Diabetes and Diabetic Vascular Complications: Studies With FP15, A Novel Potent Peroxynitrite Decomposition Catalyst

  • Published:
Molecular Medicine Aims and scope Submit manuscript

Abstract

Background

Peroxynitrite is a cytotoxic oxidant formed from nitric oxide (NO) and superoxide. Tyrosine nitration, a footprint of peroxynitrite, has been demonstrated in the pancreatic islets as well as in the cardiovascular system of diabetic subjects. Delineation of the pathogenetic role of peroxynitrite in disease conditions requires the use of potent, in vivo active peroxynitrite decomposition catalysts. The aim of the current work was to produce a potent peroxynitrite decomposition catalyst and to test its effects in rodent models of diabetes and its complications.

Methods

FP15 was synthesized and analyzed using standard chemical methods. Diabetes was triggered by the administration of streptozotocin. Tyrosine nitration was measured immunohistochemically. Cardiovascular and vascular measurements were conducted according to standard physiologic methods.

Results

FP15, a potent porphyrinic peroxynitrite decomposition catalyst, potently inhibited tyrosine nitration and peroxynitrite-induced cytotoxicity in vitro and in vivo. FP15 treatment (3–10 mg/kg/d) dose dependently and reduced the incidence and severity of diabetes mellitus in rats subjected to multiple low doses of streptozotocin, as well as in nonobese mice developing spontaneous autoimmune diabetes. Furthermore, treatment with FP15 protected against the development of vascular dysfunction (loss of endothelium-dependent relaxations) and the cardiac dysfunction (loss of my-ocardial contractility) in diabetic mice. FP15 treatment reduced tyrosine nitration in the diabetic pancreatic islets.

Conclusions

The current results demonstrate the importance of endogenous peroxynitrite generation in the pathogenesis of autoimmune diabetes and diabetic cardiovascular complications. Peroxynitrite decomposition catalysts may be of therapeutic utility in diabetes and other pathophysiologic conditions.

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
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Beckman JS, Beckman TW, Chen J, Marshall PA, Freeman BA. (1990) Apparent hydroxyl radical production by peroxynitrite: implications for endothelial injury from nitric oxide and superoxide. Proc. Natl. Acad. Sci. U. S. A. 87: 1620–1624.

    Article  CAS  Google Scholar 

  2. Ischiropoulos H, Zhu L, Chen J, et al. (1992) Peroxynitrite-mediated tyrosine nitration catalyzed by superoxide dismutase. Arch. Biochem. Biophys. 298: 431–37.

    Article  CAS  Google Scholar 

  3. Estevez AG, Radi R, Barbeito L, Shin JT, Thompson JA, Beckman JS. (1995) Peroxynitrite-induced cytotoxicity in PC12 cells: evidence for an apoptotic mechanism differentially modulated by neurotrophic factors. J. Neurochem. 65: 1543–1550.

    Article  CAS  Google Scholar 

  4. Szabó C, Zingarelli B, O’Connor M, Salzman AL. (1996) DNA strand breakage, activation of poly (ADP-ribose) synthetase, and cellular energy depletion are involved in the cytotoxicity of macrophages and smooth muscle cells exposed to peroxynitrite. Proc. Natl. Acad. Sci. U. S. A. 93: 1753–1758.

    Article  Google Scholar 

  5. Virág L, Scott GS, Marmer D, Cuzzocrea S, Salzman AL, Szabó C. (1998) Peroxynitrite-induced thymocyte apoptosis: the role of caspases and poly (ADP-ribose) synthetase (PARS) activation. Immunology 94: 345–355.

    Article  Google Scholar 

  6. Estevez AG, Spear N, Manuel SM, et al. (1998) Nitric oxide and superoxide contribute to motor neuron apoptosis induced by trophic factor deprivation. J. Neurosci. 18: 923–939.

    Article  CAS  Google Scholar 

  7. Beckman JS, Koppenol WH. (1996) Nitric oxide, superoxide, and peroxynitrite: the good, the bad, and ugly. Am. J. Physiol. 271: C1424–C1437.

    Article  CAS  Google Scholar 

  8. Szabó C. (1996) The pathophysiological role of peroxynitrite in shock, inflammation, and ischemia-reperfusion injury. Shock6: 79–88.

    Article  Google Scholar 

  9. Greenacre SA, Ischiropoulos H. (2001) Tyrosine nitration: localisation, quantification, consequences for protein function and signal transduction. Free Radic. Res. 34: 541–581.

    Article  CAS  Google Scholar 

  10. Suarez-Pinzon WL, Szabó C, Rabinovitch A. (1997) Development of autoimmune diabetes in NOD mice is associated with the formation of peroxynitrite in pancreatic islet beta-cells. Diabetes46: 907–911.

    Article  CAS  Google Scholar 

  11. Kastenbauer S, Koedel U, Becker BF, Pfister HW. (2002) Oxidative stress in bacterial meningitis in humans. Neurology58: 186–191.

    Article  CAS  Google Scholar 

  12. Soriano FG, Virâg L, Jagtap P, et al. (2001) Diabetic endothelial dysfunction: the role of poly(ADP-ribose) polymerase activation. Nature Med. 7: 108–113.

    Article  CAS  Google Scholar 

  13. Thuraisingham RC, Nott CA, Dodd SM, Yaqoob MM. (2000) Increased nitrotyrosine staining in kidneys from patients with diabetic nephropathy. Kidney Int. 57: 968–972.

    Article  Google Scholar 

  14. Szabó C, Cuzzocrea S, Zingarelli B, O’Connor M, Salzman AL. (1997) Endothelial dysfunction in a rat model of endotoxic shock. Importance of the activation of poly (ADP-ribose) synthetase by peroxynitrite. J. Clin. Invest. 100: 723–735.

    Article  Google Scholar 

  15. Villa LM, Salas E, Darley-Usmar VM, Radomski MW, Moncada S. (1994) Peroxynitrite induces both vasodilatation and impaired vascular relaxation in the isolated perfused rat heart. Proc. Natl. Acad. Sci. U. S. A. 91: 2383–2387.

    Google Scholar 

  16. Ferdinandy P, Panas D, Schulz R. (1999) Peroxynitrite contributes to spontaneous loss of cardiac efficiency in isolated working rat hearts. Am. J. Physiol. 276: H1861–H1867.

    CAS  PubMed  Google Scholar 

  17. Digerness SB, Harris KD, Kirklin JW, et al. (1999) Peroxynitrite irreversibly decreases diastolic and systolic function in cardiac muscle. Free Radic. Biol. Med. 27: 1386–1392.

    Article  CAS  Google Scholar 

  18. Pasternack RF, Gillies BS, Stromsted JP. (1978) Substitution reactions of a water-soluble metalloporphyrin with azide and 1,1,3,3-tetramethyl-2-thiourea. Bioinorg Chem. 8: 33–44.

    Article  CAS  Google Scholar 

  19. Shimanovich R, Groves JT. (2001) Mechanisms of peroxynitrite decomposition catalyzed by FeTMPS, a bioactive sulfonated iron porphyrin. Arch. Biochem. Biophys. 387: 307–317.

    Article  CAS  Google Scholar 

  20. Mabley JG, Cunningham JM, John N, Di Matteo MA, Green IC. (1997) Transforming growth factor beta 1 prevents cytokine-mediated inhibitory effects and induction of nitric oxide synthase in the RINm5F insulin-containing beta-cell line. J. Endocrinol. 155: 567–575.

    Article  CAS  Google Scholar 

  21. Mabley JG, Suarez-Pinzon WL, Hasko G, et al. (2001) Inhibition of poly (ADP-ribose) synthetase by gene disruption or inhibition with 5-iodo-6-amino-1,2-benzopyrone protects mice from multiple-low-dose-streptozotocin-induced diabetes. Br. J. Pharmacol. 133: 909–919.

    Article  CAS  Google Scholar 

  22. Liaudet L, Szabo E, Timashpolsky L, Virag L, Cziraki A, Szabo C. (2001) Suppression of poly (ADP-ribose) polymerase activation by 3-aminobenzamide in a rat model of myocardial infarction: long-term morphological and functional consequences. Br. J. Pharmacol. 133: 1424–1430.

    Article  CAS  Google Scholar 

  23. Lee J, Hunt JA, Groves JT. (1998) Manganese porphyrins as redox-coupled peroxynitrite reductases. J. Am. Chem. Soc. 120: 6053–6061.

    Article  CAS  Google Scholar 

  24. Radi R, Beckman JS, Bush KM, Freeman BA. (1991) Peroxynitrite-induced membrane lipid peroxidation: the cytotoxic potential of superoxide and nitric oxide. Arch. Biochem. Biophys. 288: 481–487.

    Article  CAS  Google Scholar 

  25. Klebanoff SJ. (1993) Reactive nitrogen intermediates and antimicrobial activity: role of nitrite. Free Radic. Biol. Med. 14: 351–360.

    Article  CAS  Google Scholar 

  26. Estevez AG, Crow JP, Sampson JB, et al. (1999) Induction of nitric oxide-dependent apoptosis in motor neurons by zinc-deficient superoxide dismutase. Science286: 2498–2500.

    Article  CAS  Google Scholar 

  27. Bohle DS. (1998) Pathophysiological chemistry of nitric oxide and its oxygenation by-products. Curr. Opin. Chem. Biol. 2: 194–200.

    Article  CAS  Google Scholar 

  28. Groves JT. (1999) Peroxynitrite: reactive, invasive and enigmatic. Curr. Opin. Chem. Biol. 3: 226–235.

    Article  CAS  Google Scholar 

  29. Greenacre SA, Ischiropoulos H. (2001) Tyrosine nitration: localisation, quantification, consequences for protein function and signal transduction. Free Radic. Res. 34: 541–581.

    Article  CAS  Google Scholar 

  30. Shi X, Rojanasakul Y, Gannett P, et al. (1994) Generation of thiyl and ascorbyl radicals in the reaction of peroxynitrite with thiols and ascorbate at physiological pH. J. Inorg. Biochem. 56: 77–86.

    Article  CAS  Google Scholar 

  31. Balavoine GG, Geletti YV, Bejan D. (1997) Catalysis of peroxynitrite reactions by manganese and iron porphyrins. Nitric Oxide1: 507–521.

    Article  CAS  Google Scholar 

  32. Lee J, Hunt JA, Groves JT. (1997) Rapid decomposition of peroxynitrite by manganese porphyrin-antioxidant redox-couples. Bioorg. Med. Chem. Lett. 7: 2913–2918.

    Article  CAS  Google Scholar 

  33. Groves JT, Lee J, Marla S. (1997) Detection and characterization of an oxo-manganese(V) porphyrin complex by rapid-mixing stopped-flow spectrophotometry. J. Am. Chem. Soc. 119: 6269–6273.

    Article  CAS  Google Scholar 

  34. Salvemini D, Wang ZQ, Stern MK, Currie MG, Misko TP. (1998) Peroxynitrite decomposition catalysts: therapeutics for peroxynitrite-mediated pathology. Proc. Natl. Acad. Sci. U. S. A. 95: 2659–2663.

    Article  CAS  Google Scholar 

  35. Lymar SV, Hurst JK. (1996) Carbon dioxide: physiological catalyst for peroxynitrite-mediated cellular damage or cellular protectant? Chem. Res. Toxicol. 9: 845–850.

    Article  CAS  Google Scholar 

  36. Delaney CA, Tyrberg B, Bouwens L, Vaghef H, Hellman B, Eizirik DL. (1996) Sensitivity of human pancreatic islets to peroxynitrite-induced cell dysfunction and death. FEBS Lett. 394: 300–306.

    Article  CAS  Google Scholar 

  37. Suarez-Pinzon WL, Mabley JG, Strynadka K, Power RF, Szabo C, Rabinovitch A. (2001) An inhibitor of inducible nitric oxide synthase and scavenger of peroxynitrite prevents diabetes development in NOD mice. J. Autoimmun. 16: 449–455.

    Article  CAS  Google Scholar 

  38. Flodstrom M, Tyrberg B, Eizirik DL, Sandler S. (1999) Reduced sensitivity of inducible nitric oxide synthase-deficient mice to multiple low-dose streptozotocin-induced diabetes. Diabetes48: 706–713.

    Article  CAS  Google Scholar 

  39. Zouki C, Zhang SL, Chan JS, Filep JG. (2001) Peroxynitrite induces integrin-dependent adhesion of human neutrophils to endothelial cells via activation of the Raf-1/MEK/Erk pathway. FASEB J. 15: 25–27.

    Article  CAS  Google Scholar 

  40. Cuzzocrea S, Misko TP, Costantino G, et al. (2000) Beneficial effects of peroxynitrite decomposition catalyst in a rat model of splanchnic artery occlusion and reperfusion. FASEB J. 14: 1061–1072.

    Article  CAS  Google Scholar 

  41. Soriano FG, Mabley JG, Pacher P, Liaudet L, Szabó C. (2001) Rapid reversal of the diabetic endothelial dysfunction by pharmacological inhibition of poly(ADP-ribose) polymerase. Circ. Res. 89: 684–691.

    Article  CAS  Google Scholar 

  42. Sowers JR, Epstein M, Frohlich ED. (2001) Diabetes, hypertension, and cardiovascular disease: an update. Hypertension37: 1053–1059.

    Article  CAS  Google Scholar 

  43. Frustaci A, Kajstura J, Chimenti C, et al. (2000) Myocardial cell death in human diabetes. Circ. Res. 87: 1123–1132.

    Article  CAS  Google Scholar 

  44. Kajstura J, Fiordaliso F, Andreoli AM, et al. (2001) IGF-1 overexpression inhibits the development of diabetic car-diomyopathy and angiotensin II-mediated oxidative stress. Diabetes50: 1414–1424.

    Article  CAS  Google Scholar 

  45. Mihm MJ, Coyle CM, Schanbacher BL, Weinstein DM, Bauer JA. (2001) Peroxynitrite induced nitration and inactivation of myofibrillar creatine kinase in experimental heart failure. Cardiovasc. Res. 49: 798–807.

    Article  CAS  Google Scholar 

  46. Turko IV, Marcondes S, Murad F. (2001) Diabetes-associated nitration of tyrosine and inactivation of succinyl-CoA:3-oxoacid CoA-transferase. Am. J. Physiol. 281: H2289–H2294.

    CAS  Google Scholar 

  47. Zhang X, Chen J, Graham SH, et al. (2002) Intranuclear localization of apoptosis-inducing factor and large scale DNA fragmentation after traumatic brain injury in rats and in neuronal cultures exposed to peroxynitrite. J. Neurochem. 82: 181–191.

    Article  CAS  Google Scholar 

  48. Bianchi C, Wakiyama H, Faro R, et al. (2002) A novel peroxynitrite decomposition catalyst (FP-15) reduces heart infarct size in a model of acute ischemia-reperfusion. Ann. Thorac. Surg. (in press).

  49. Pacher P, Liaudet L, Bai P, Virág L, Mabley JG, Szabó C. (2002) A potent peroxynitrite decomposition catalyst, FP15, protects against the development of doxorubicin-induced heart failure. FASEB J. 16: A177 (abstract).

    Article  Google Scholar 

  50. Naidu BV, Krishnadasan B, Fraga C, et al. (2002) The critical role of reactive nitrogen species in lung ischemia reperfusion injury. J. Heart Lung Transplant. 21: 135 (abstr).

    Article  Google Scholar 

  51. Mabley JG, Liaudet L, Pacher P, Southan GJ, Salzman AL, Szabó C. (2002) Beneficial effects of the peroxynitrite decomposition catalyst FP15 in murine models of arthritis and colitis. Mol. Med. 8: 581–590.

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

We are grateful for support of this research through grants from the National Institutes of Health (R01GM60915 and R01HL71246 to C. S. and R01GM36928 to J. T. G.).

Author information

Authors and Affiliations

  1. Inotek Pharmaceuticals Corporation, Beverly, Massachusetts, USA

    Csaba Szabó, Jon G. Mabley, Pál Pacher, László Virág, John H. Van Duzer, William Williams & Andrew L. Salzman

  2. Department of Surgery, New Jersey Medical School, University of Medicine and Dentistry New Jersey, Newark, New Jersey, USA

    Csaba Szabó & Francisco G. Soriano

  3. Department of Chemistry, Princeton University, Princeton, New Jersey, 08544-1009, USA

    Suzanne M. Moeller, Roman Shimanovich & John T. Groves

Authors
  1. Csaba Szabó
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jon G. Mabley
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Suzanne M. Moeller
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Roman Shimanovich
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Pál Pacher
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. László Virág
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Francisco G. Soriano
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. John H. Van Duzer
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. William Williams
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Andrew L. Salzman
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. John T. Groves
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to John T. Groves.

Additional information

Contributed by C. Szabó

Rights and permissions

Reprints and permissions

About this article

Cite this article

Szabó, C., Mabley, J.G., Moeller, S.M. et al. Part I: Pathogenetic Role of Peroxynitrite in the Development of Diabetes and Diabetic Vascular Complications: Studies With FP15, A Novel Potent Peroxynitrite Decomposition Catalyst. Mol Med 8, 571–580 (2002). https://doi.org/10.1007/BF03402167

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF03402167

Keywords

Search

Navigation