Peroxynitrite decomposition catalysts prevent myocardial dysfunction and inflammation in endotoxemic rats

Lancel, Steve; Tissier, Stéphanie; Mordon, Serge; Maréchal, Xavier; Depontieu, Florence; Scherpereel, Arnaud; Chopin, C.; Nevière, Rémi

doi:10.1016/j.jacc.2004.01.047

Cited by 90 publications

(57 citation statements)

References 54 publications

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“…This contrasts with previous findings using iron-based metalloporphyrinic agents as peroxynitrite decomposition catalysts, which resulted in decreased myocardial myeloperoxidase activity in septic rats (Lancel et al, 2004) and decreased myeloperoxidase activity in lung reperfusion injury (Naidu et al, 2003). These discrepancies are possibly related to differences in the type of catalyst used or differences in experimental models.…”

contrasting

confidence: 82%

“…These agents catalyze the isomerization of peroxynitrite, resulting in its decomposition to the less reactive anion, nitrate, thereby, decreasing the levels of the potent oxidizing and nitrating species, peroxynitrite. In previous studies, iron (III) metalloporphyrin-based peroxynitrite decomposition catalysts, including 5,10,15,20-tetrakis-[4-sulfonatophenyl]-porphyrinato-iron [III] and FeCl tetrakis-2-(triethylene glycol monomethyl ether) pyridyl porphyrin have been shown to have protection in models of myocardial infarction (Bianchi et al, 2002) and cytokine-induced (Ferdinandy et al, 2000) or doxorubicin-induced (Pacher et al, 2003) or endotoxin-induced (Lancel et al, 2004) cardiac dysfunction. In the present study, we examined the antirejection, anti-inflammatory, and antiapoptotic mechanisms of action of the novel metalloporphyrinic peroxynitrite decomposition catalyst WW85 in experimental cardiac transplantation.…”

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confidence: 99%

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Protective Mechanisms of a Metalloporphyrinic Peroxynitrite Decomposition Catalyst, WW85, in Rat Cardiac Transplants

Pieper¹,

Nilakantan²,

Chen³

et al. 2005

J Pharmacol Exp Ther

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Nitric oxide (NO) derived from inducible NO synthase has been implicated in cardiac rejection. However, little is known about the role of the reactive nitrogen species peroxynitrite. We examined the protective actions of a peroxynitrite decomposition catalyst, WW85, in an experimental model of acute cardiac rejection. Heterotopic, abdominal transplantation of rat donor hearts was performed. Groups included isografts, allografts, or allografts treated with WW85, cyclosporine, or cyclosporine ϩ WW85. We determined graft survival, histological rejection, and graft function (by in situ sonomicrometry). Intragraft biochemical analysis of cytokines and proapoptotic and antiapoptotic gene expression using reverse transcriptase-polymerase chain reaction were determined. Treatment with WW85 or cyclosporine alone prolonged graft survival, improved graft function, and decreased histological rejection. Graft survival was further significantly (P Ͻ 0.001) enhanced by combination treatment. A decrease was also shown in nitrotyrosine, poly(ADP-ribose) polymerase (PARP) activation, and lipid peroxide formation by WW85 that was potentiated when given in combination with cyclosporine. Benefits could not be ascribed to changes in intragraft myeloperoxidase activity. Only combination therapy produced significant decreases in inflammatory cytokine gene expression, suggesting that WW85 acted primarily downstream of these stimuli. In general, WW85 had no direct action on expression of the proapoptotic gene, Fas ligand; however, WW85 given alone or with cyclosporine enhanced expression of antiapoptotic genes Bcl-2 and Bcl-xL. Collectively, these findings suggest a protective action of the peroxynitrite decomposition catalyst WW85 on graft rejection that is independent of any action on leukocyte sequestration and cytokine gene expression. Rather, effects seem to be downstream on decreased protein nitration, decreased lipid peroxidation, and decreased PARP activation.

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confidence: 82%

mentioning

confidence: 99%

Protective Mechanisms of a Metalloporphyrinic Peroxynitrite Decomposition Catalyst, WW85, in Rat Cardiac Transplants

Pieper¹,

Nilakantan²,

Chen³

et al. 2005

J Pharmacol Exp Ther

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“…Peroxynitrite, rather than NO per se, has been shown to impair muscle contractility during sepsis by its ability to denature proteins, perturb calcium flux, and depress mitochondrial respiration during experimental sepsis (115,116). In contrast, neutralization of peroxynitrite improved cardiac dysfunction in a rodent model of sepsis (117). In human septic hearts, increased expression of iNOS and significant amounts of peroxynitrite were found (51).…”

Section: Nitric Oxide and Peroxynitritementioning

confidence: 99%

Molecular Events in the Cardiomyopathy of Sepsis

Flierl

Rittirsch

Huber‐Lang

et al. 2008

Mol Med

108

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Septic cardiomyopathy is a well-described complication of severe sepsis and septic shock. However, the interplay of its underlying mechanisms remains enigmatic. Consequently, we constantly add to our pathophysiological understanding of septic cardiomyopathy. Various cardiosuppressive mediators have been discovered, as have multiple molecular mechanisms (alterations of myocardial calcium homeostasis, mitochondrial dysfunction, and myocardial apoptosis) that may be involved in myocardial dysfunction during sepsis. Finally, the detrimental roles of nitric oxide and peroxynitrite have been unraveled. Here, we describe our present understanding of systemic, supracellular, and cellular molecular mechanisms involved in sepsis-induced myocardial suppression. SYSTEMIC, SUPRACELLULAR MECHANISMS Decreased Coronary Blood FlowOne of the first suggestions was that reduced coronary perfusion in the septic heart might be responsible for a setting of global cardiac ischemia. This hypothesis was soon abandoned after direct measurements of coronary blood flow were obtained, showing no reduced, but rather increased, coronary blood flow (22,23). In later studies, however, increased levels of plasma troponin were observed and correlated with the severity of myocardial depression during sepsis and septic shock (24). Myocardial necrosis could not be observed in patients who died from septic shock (3,25), however, raising the question whether increases in troponin were due to cytokine-induced, transient increases in cardiomyocyte membrane permeability to troponin. To date, this remains to be determined. Alterations of MicrovasculatureThere is now increasing evidence that sepsis and septic shock leads to changes of the myocardial microvasculature. In a canine model of endotoxemia, maldistribution of heterogeneous coronary blood flow has been reported (26). These findings might be caused by endothelial swelling and nonocclusive intravascular fibrin deposits in the microvasculature (27). In parallel, activated cardiomyocytes from septic mice promoted transendothelial migration and activation of circulating neutrophils into the interstitium (28) where these cells may augment the sepsis-induced intracardial inflammation, and contribute to an increased vascular leakage, which has been described to also impair cardiac function and compliance secondary to myocardial edema (29,30). Yet, studies have failed to confirm cellular hypoxia in a murine sepsis model (31). Cardiosuppressing Circulating Proinflammatory MediatorsAnother hypothesis suggested circulating myocardium-depressing factors as the cause of septic cardiomyopathy (32). Parrillo et al. (33) confirmed the existence of a cardiodepressant substance by incubating isolated rat cardiomyocytes with serum obtained from septic shock patients, leading to decreased amplitude and velocity of cardiomyocyte shortening. Levels of cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and the complement anaphylatoxin, C5a, are known to be elevated in the circulation during sepsis an...

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“…MEG also displays different anti-inflammatory effects, including the inhibition of neutrophil migration and thus can inhibit the two main pathways of 3-nitrotyrosine formation (24,32).…”

Section: Parasitemia and Mortalitymentioning

confidence: 99%

Protein 3-nitrotyrosine formation during Trypanosoma cruzi infection in mice

Naviliat

Gualco

Cayota

et al. 2005

Braz J Med Biol Res

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Tyrosine nitration is a post-translational modification resulting from the addition of a nitro (-NO 2 ) group to the ortho-position of tyrosine residues. Detection of protein 3-nitrotyrosine is regarded as a marker of nitro-oxidative stress and is observed in inflammatory processes. The formation and role of nitrating species in the control and myocardiopathy of T. cruzi infection remain to be studied. We investigated the levels of • NO and protein 3-nitrotyrosine in the plasma of C3H and BALB/c mice and pharmacologically modulated their production during the acute phase of T. cruzi infection. We also looked for protein 3-nitrotyrosine in the hearts of infected animals. Our results demonstrated that C3H animals produced higher amounts of • NO than BALB/c mice, but their generation of peroxynitrite was not proportionally enhanced and they had higher parasitemias. While N G -nitroarginine methyl ester treatment abolished • NO production and drastically augmented the parasitism, mercaptoethylguanidine and guanidoethyl disulfide, at doses that moderately reduced the • NO and 3-nitrotyrosine levels, paradoxically diminished the parasitemia in both strains. Nitrated proteins were also demonstrated in myocardial cells of infected mice. These data suggest that the control of T. cruzi infection depends not only on the capacity to produce • NO, but also on its metabolic fate, including the generation of nitrating species that may constitute an important element in parasite resistance and collateral myocardial damage.

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Peroxynitrite decomposition catalysts prevent myocardial dysfunction and inflammation in endotoxemic rats

Abstract: These observations suggest that the beneficial effects of MEG and FeTPPS on endotoxin-induced myocardial contractile dysfunction could be related to the unique effects of these compounds on cardiovascular inflammation processes.

Cited by 90 publications

References 54 publications

Protective Mechanisms of a Metalloporphyrinic Peroxynitrite Decomposition Catalyst, WW85, in Rat Cardiac Transplants

Protective Mechanisms of a Metalloporphyrinic Peroxynitrite Decomposition Catalyst, WW85, in Rat Cardiac Transplants

Molecular Events in the Cardiomyopathy of Sepsis

Protein 3-nitrotyrosine formation during Trypanosoma cruzi infection in mice

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