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(Circulation Research. 2001;88:e12.)
© 2001 American Heart Association, Inc.

Letter to the Editor

Peroxynitrite: Toxic or Protective in the Heart?

Péter Ferdinandy¹

¹ Cardiovascular Research Group, Department of Biochemistry, University of Szeged, Szeged, Hungary

Richard Schulz²

² Cardiovascular Research Group, Departments of Pediatrics and Pharmacology, University of Alberta, Edmonton, Alberta, Canada, richard.schulz@ualberta.ca

	Peroxynitrite: Toxic or Protective in the Heart?

Top Peroxynitrite: Toxic or... References

 
To the Editor:

The literature is somewhat controversial as to whether peroxynitrite (ONOO^–) is either cytotoxic or cytoprotective. An Editorial by Vinten-Johansen¹ recently suggested that deleterious effects of ONOO^– in the heart are predominantly observed in in vitro or ex vivo crystalloid buffer–perfused systems; however, ONOO^– is cardioprotective if applied in vivo. Does the exogenous administration of ONOO^– accurately reflect pathological conditions in which the endogenous generation of ONOO^– within cells is enhanced?

Because of the short half-life of ONOO^– at physiological pH, it has very little chance to reach its cellular targets when it is applied via the blood, as it rapidly reacts with plasma proteins and thiols such as glutathione and cysteine. Thus, ONOO^– is likely to be detoxified before it has a chance to reach tissues downstream of the injection site, let alone the intracellular compartment.² ONOO^– forms S-nitrosothiols when it combines with thiol groups,³ which then act as nitric oxide (NO) donors. Because NO itself is a cardioprotective and antioxidant molecule,⁴ protection from noxious stimuli may result when exogenous ONOO^– is administered intravenously. Accordingly, exogenously administered ONOO^– was shown to inhibit leukocyte-endothelial cell interactions and to protect against ischemia/reperfusion injury in rats in vivo.⁵ Intraventricular infusion of ONOO^– reduced myocardial infarct size and preserved coronary endothelium after ischemia and reperfusion in cats,⁶ an effect that was mediated by the intermediate formation of S-nitrosothiols.⁷

Exogenously applied ONOO^–, however, has been shown to be detrimental to cellular functions when it was applied in crystalloid buffer systems, in which the concentrations of extracellular antioxidants and both free and protein-bound thiols are limited. In this case, exogenous ONOO^– and its toxic metabolites have a greater chance to reach their cellular targets and cause injury. This is, of course, dependent upon the concentration of ONOO^– and the duration of exposure. We have shown that continuous infusion of 40 but not 4 µmol/L ONOO^– into isolated working rat hearts impaired cardiac contractile function within 45 minutes.⁸ Authentic ONOO^– inhibited contractile function of cardiac myocytes⁹ and isolated rat papillary muscle.¹⁰ Administration of the ONOO^– generator 3-morpholinosydnonimine (SIN-1) exerted either cardiodepression in crystalloid buffer–perfused or cardioprotection in blood-perfused rat hearts.¹¹ Similar results were obtained using either crystalloid or blood cardioplegia in dogs.¹² One can conclude that exogenous ONOO^– is toxic when applied in crystalloid perfused hearts; however, it can be protective under experimental conditions in which ONOO^– first reacts with thiol groups, thereby forming NO donors.

It is, however, questionable whether antioxidants such as thiols are of sufficient concentration to adequately detoxify ONOO^– at the site of its endogenous formation, especially under conditions of ischemia/reperfusion or after expression of inducible NO synthase. To our knowledge, there is no literature showing any tissue protective effect of endogenously formed ONOO^–. In contrast, many studies show that enhanced formation of ONOO^– in the myocardium is cytotoxic to the heart and contributes to ischemia/reperfusion injury both in vitro^{13 14} and in vivo,¹⁵ the spontaneous loss of cardiac function¹⁶ as well as cytokine-induced myocardial contractile failure in isolated rat hearts¹⁷ and in dogs in vivo,¹⁸ myocardial dysfunction after doxorubicin treatment of mice in vivo,¹⁹ autoimmune myocarditis²⁰ and acute allograft rejection²¹ in rats, myocardial inflammation in humans,²² and cardiomyocyte apoptosis.²³ Many of these studies show a correlation between ONOO^– formation and deterioration of cardiac function.

Taken together, there is a consensus that endogenously formed ONOO^– contributes to myocardial injury resulting from ischemia and reperfusion injury as well as systemic inflammatory response syndrome. Specific pharmacological targeting of ONOO^– is an exciting new strategy to protect the heart from oxidant stress injury.¹⁷

	Acknowledgments

 
We acknowledge the support of the Canadian Institutes of Health Research (MT-11563) as well as a North Atlantic Treaty Organization Cooperative Linkage grant (LST.CLG.976650).

	References

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1. Vinten-Johansen J. Physiological effects of peroxynitrite: potential products of the environment. Circ Res. 2000;87:170–172.[Free Full Text]
2. Ishida H, Genka C, Nakazawa H. Application of authentic peroxynitrite to biological materials. Methods Enzymol. 1999;301:402–409.[Medline] [Order article via Infotrieve]
3. Moro MA, Darley-Usmar VM, Goodwin DA, Read NG, Zamora-Pino R, Feelisch M, Radomski MW, Moncada S. Paradoxical fate and biological action of peroxynitrite on human platelets. Proc Natl Acad Sci U S A. 1994;91:6702–6706.[Abstract/Free Full Text]
4. Rubbo H, Darley-Usmar V, Freeman BA. Nitric oxide regulation of tissue free radical injury. Chem Res Toxicol. 1996;9:809–820.[Medline] [Order article via Infotrieve]
5. Lefer DJ, Scalia R, Campbell B, Nossuli T, Hayward R, Salamon M, Grayson J, Lefer AM. Peroxynitrite inhibits leukocyte-endothelial cell interactions and protects against ischemia-reperfusion injury in rats. J Clin Invest. 1997;99:684–691.[Medline] [Order article via Infotrieve]
6. Nossuli TO, Hayward R, Scalia R, Lefer AM. Peroxynitrite reduces myocardial infarct size and preserves coronary endothelium after ischemia and reperfusion in cats. Circulation. 1997;96:2317–2324.[Abstract/Free Full Text]
7. Nossuli TO, Hayward R, Jensen D, Scalia R, Lefer AM. Mechanisms of cardioprotection by peroxynitrite in myocardial ischemia and reperfusion injury. Am J Physiol. 1998;275:H509–H519.[Abstract/Free Full Text]
8. Schulz R, Dodge KL, Lopaschuk GD, Clanachan AS. Peroxynitrite impairs cardiac contractile function by decreasing cardiac efficiency. Am J Physiol. 1997;272:H1212–H1219.[Abstract/Free Full Text]
9. Ishida H, Ichimori K, Hirota Y, Fukahori M, Nakazawa H. Peroxynitrite-induced cardiac myocyte injury. Free Radic Biol Med. 1996;20:343–350.[Medline] [Order article via Infotrieve]
10. Digerness SB, Harris KD, Kirklin JW, Urthaler F, Viera L, Beckman JS, Darley-Usmar V. Peroxynitrite irreversibly decreases diastolic and systolic function in cardiac muscle. Free Radic Biol Med. 1999;27:1386–1392.[Medline] [Order article via Infotrieve]
11. Ma XL, Gao F, Lopez BL, Christopher TA, Vinten-Johansen J. Peroxynitrite, a two-edged sword in post-ischemic myocardial injury-dichotomy of action in crystalloid- versus blood-perfused hearts. J Pharmacol Exp Ther. 2000;292:912–920.[Abstract/Free Full Text]
12. Ronson RS, Thourani VH, Ma XL, Katzmark SL, Han D, Zhao ZQ, Nakamura M, Guyton RA, Vinten-Johansen J. Peroxynitrite, the breakdown product of nitric oxide, is beneficial in blood cardioplegia but injurious in crystalloid cardioplegia. Circulation. 1999;100(suppl II):II-384–II-391.
13. Yasmin W, Strynadka KD, Schulz R. Generation of peroxynitrite contributes to ischemia-reperfusion injury in isolated rat hearts. Cardiovasc Res. 1997;33:422–432.[Abstract/Free Full Text]
14. Wang PH, Zweier JL. Measurement of nitric oxide and peroxynitrite generation in the postischemic heart: evidence for peroxynitrite-mediated reperfusion injury. J Biol Chem. 1996;271:29223–29230.[Abstract/Free Full Text]
15. Liu PT, Hock CE, Nagele R, Wong PYK. Formation of nitric oxide, superoxide, and peroxynitrite in myocardial ischemia-reperfusion injury in rats. Am J Physiol. 1997;272:H2327–H2336.[Abstract/Free Full Text]
16. Ferdinandy P, Panas D, Schulz R. Peroxynitrite contributes to spontaneous loss of cardiac efficiency in isolated working rat hearts. Am J Physiol. 1999;276:H1861–H1867.[Abstract/Free Full Text]
17. Ferdinandy P, Danial H, Ambrus I, Rothery RA, Schulz R. Peroxynitrite is a major contributor to cytokine-induced myocardial contractile failure. Circ Res. 2000;87:241–247.[Abstract/Free Full Text]
18. Oyama J, Shimokawa H, Momii H, Cheng X, Fukuyama N, Arai Y, Egashira K, Nakazawa H, Takeshita A. Role of nitric oxide and peroxynitrite in the cytokine-induced sustained myocardial dysfunction in dogs in vivo. J Clin Invest. 1998;101:2207–2214.[Medline] [Order article via Infotrieve]
19. Weinstein DM, Mihm MJ, Bauer JA. Cardiac peroxynitrite formation and left ventricular dysfunction following doxorubicin treatment in mice. J Pharmacol Exp Ther. 2000;294:396–401.[Abstract/Free Full Text]
20. Ishiyama S, Hiroe M, Nishikawa T, Abe S, Shimojo T, Ito H, Ozasa S, Yamakawa K, Matsuzaki M, Mohammed MU, Nakazawa H, Kasajima T, Marumo F. Nitric oxide contributes to the progression of myocardial damage in experimental autoimmune myocarditis in rats. Circulation. 1997;95:489–496.[Abstract/Free Full Text]
21. Sakurai M, Fukuyama N, Iguchi A, Akimoto H, Ohmi M, Yokoyama H, Nakazawa H, Tabayashi K. Quantitative analysis of cardiac 3-L-nitrotyrosine during acute allograft rejection in an experimental heart transplantation. Transplantation. 1999;68:1818–1822.[Medline] [Order article via Infotrieve]
22. Kooy NW, Lewis SJ, Royall JA, Ye YZ, Kelly DR, Beckman, JS. Extensive tyrosine nitration in human myocardial inflammation: evidence for the presence of peroxynitrite. Crit Care Med. 1997;25:812–819.[Medline] [Order article via Infotrieve]
23. Arstall MA, Sawyer DB, Fukazawa R, Kelly RA. Cytokine-mediated apoptosis in cardiac myocytes: the role of inducible nitric oxide synthase induction and peroxynitrite generation. Circ Res. 1999;85:829–840.[Abstract/Free Full Text]

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