Peroxynitrite is a major trigger of cardiomyocyte apoptosis in vitro and in vivo

Levrand, Sandra; Vannay-Bouchiche, Christine; Pesse, Benoît; Pacher, Pál; Feihl, François; Waeber, Bernard; Liaudet, Lucas

doi:10.1016/j.freeradbiomed.2006.04.034

Cited by 131 publications

(114 citation statements)

References 55 publications

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“…Using flow cytometry, fluorescent and confocal microscopy, biochemistry, and molecular biology techniques, we also demonstrated that DOX, similarly to exogenously applied peroxynitrite (22), induces marked dose-dependent increases in cellular NT formation, dissipation of mitochondrial membrane potential, cytochrome c release, and execution of the mitochon- drial phase of caspase-3-dependent apoptosis in H9c2 cardiomyocytes. Likewise, as observed in an in vivo model, these proapoptotic effects of DOX (similar to the effects of exogenously applied peroxynitrite) could be prevented by two different PSs in vitro (Figs.…”

Section: Discussionmentioning

confidence: 72%

Role of superoxide, nitric oxide, and peroxynitrite in doxorubicin-induced cell death in vivo and in vitro

Mukhopadhyay

Rajesh

Bátkai

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

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Mukhopadhyay P, Rajesh M, Bátkai S, Yoshihiro K, Haskó G, Liaudet L, Szabó C, Pacher P. Role of superoxide, nitric oxide, and peroxynitrite in doxorubicin-induced cell death in vivo and in vitro. Am J Physiol Heart Circ Physiol 296: H1466 -H1483, 2009. First published March 13, 2009 doi:10.1152/ajpheart.00795.2008.-Doxorubicin (DOX) is a potent available antitumor agent; however, its clinical use is limited because of its cardiotoxicity. Cell death is a key component in DOX-induced cardiotoxicity, but its mechanisms are elusive. Here, we explore the role of superoxide, nitric oxide (NO), and peroxynitrite in DOX-induced cell death using both in vivo and in vitro models of cardiotoxicity. Western blot analysis, real-time PCR, immunohistochemistry, flow cytometry, fluorescent microscopy, and biochemical assays were used to determine the markers of apoptosis/necrosis and sources of NO and superoxide and their production. Left ventricular function was measured by a pressure-volume system. We demonstrated increases in myocardial apoptosis (caspase-3 cleavage/activity, cytochrome c release, and TUNEL), inducible NO synthase (iNOS) expression, mitochondrial superoxide generation, 3-nitrotyrosine (NT) formation, matrix metalloproteinase (MMP)-2/MMP-9 gene expression, poly(ADP-ribose) polymerase activation [without major changes in NAD(P)H oxidase isoform 1, NAD(P)H oxidase isoform 2, p22phox , xanthine oxidase, endothelial NOS, and neuronal NOS expression] and decreases in myocardial contractility, catalase, and glutathione peroxidase activities 5 days after DOX treatment to mice. All these effects of DOX were markedly attenuated by peroxynitrite scavengers. Doxorubicin dose dependently increased mitochondrial superoxide and NT generation and apoptosis/necrosis in cardiac-derived H9c2 cells. DOX-or peroxynitrite-induced apoptosis/necrosis positively correlated with intracellular NT formation and could be abolished by peroxynitrite scavengers. DOX-induced cell death and NT formation were also attenuated by selective iNOS inhibitors or in iNOS knockout mice. Various NO donors when coadministered with DOX but not alone dramatically enhanced DOX-induced cell death with concomitant increased NT formation. DOX-induced cell death was also attenuated by cell-permeable SOD but not by cell-permeable catalase, the xanthine oxidase inhibitor allopurinol, or the NADPH oxidase inhibitors apocynine or diphenylene iodonium. Thus, peroxynitrite is a major trigger of DOX-induced cell death both in vivo and in vivo, and the modulation of the pathways leading to its generation or its effective neutralization can be of significant therapeutic benefit. heart failure; apoptosis; inducible nitric oxide synthase; hemodynamics BECAUSE OF ITS unmatched efficacy and broad-spectrum effect, doxorubicin (DOX; Adriamycin), an anthracycline antibiotic, continues to be a widely used chemotherapeutic agent to treat a variety of cancers (55) despite its potential to elicit serious dose-dependent cardiotoxicity often leading to degenerative cardiomyopathy...

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Section: Discussionmentioning

confidence: 72%

Role of superoxide, nitric oxide, and peroxynitrite in doxorubicin-induced cell death in vivo and in vitro

Mukhopadhyay

Rajesh

Bátkai

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

Self Cite

324

270

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“…Because cardiac iNOS expression was increased in post-MI rats, and normalized after 1-month NAC treatment (not shown), the improvement of hemodynamic function in NAC-treated rats more likely relied on the blunting of oxidative stress, including the neutralization of reactive nitrogen species, rather than on a NO mediated vasodilatory effect [56,57].…”

Section: Discussionmentioning

confidence: 99%

Neutral sphingomyelinase inhibition participates to the benefits of N-acetylcysteine treatment in post-myocardial infarction failing heart rats

Adamy

Mulder

Khouzami

et al. 2007

Journal of Molecular and Cellular Cardiology

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Deficiency in cellular thiol tripeptide glutathione (L-γ glutamyl-cysteinyl-glycine) determines the severity of several chronic and inflammatory human diseases that may be relieved by oral treatment with the glutathione precursor N-acetylcysteine (NAC).Here, we showed that the left ventricle (LV) of human failing heart was depleted in total glutathione by 54%. Similarly, 2-month post-myocardial infarction (MI) rats, with established chronic heart failure (CHF), displayed deficiency in LV glutathione. Onemonth oral NAC treatment normalized LV glutathione, improved LV contractile function and lessened adverse LV remodelling in 3-month post-MI rats. Biochemical studies at two time-points of NAC treatment, 3 days and 1 month, showed that inhibition of the neutral sphingomyelinase (N-SMase), Bcl-2 depletion and caspase-3 activation, were key, early and lasting events associated with glutathione repletion. Attenuation of oxidative stress, downregulation of the pro-inflammatory cytokine tumor necrosis factor-α (TNF-α) and its TNF-R1 receptor were significant after 1-month NAC treatment. These data indicate that, besides glutathione deficiency, N-SMase activation is associated with post-MI CHF progression, and that blockade of N-SMase activation participates to post-infarction failing heart recovery achieved by NAC treatment. NAC treatment in post-MI rats is a way to disrupt the vicious sTNF-α/ TNF-R1/ N-SMase cycle.

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“…9 Both elevated ROS/RNS and pro-inflammatory cytokines such as TNFα also activate various cell death signaling pathways via c-Jun, N-terminal kinase (JNK) 10-12 and p38 kinase, 12,13 leading to apoptosis and/or necrosis. 10,11,[14][15][16][17][18] Consistent with the importance of these pathways, a variety of pharmacological agents such as specific JNK inhibitors 11 and various antioxidants (e.g. ascorbate, glutathione, S-adenosylmethionine, vitamine E, etc.)…”

Section: Introductionmentioning

confidence: 99%

Oxidative Inactivation of Key Mitochondrial Proteins Leads to Dysfunction and Injury in Hepatic Ischemia Reperfusion

et al. 2008

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SummaryBackground & Aims-Ischemia-reperfusion (I/R) is a major mechanism of liver injury following hepatic surgery or transplantation. Despite numerous reports on the role of oxidative/nitrosative stress and mitochondrial dysfunction in hepatic I/R injury, the proteins that are oxidatively-modified during I/R damage are poorly characterized. This study was aimed at investigating the oxidatively-modified proteins underlying the mechanism for mitochondrial dysfunction in hepatic I/R injury. We also studied the effects of a superoxide dismutase mimetic/peroxynitrite scavenger metalloporphyrin MnTMPyP on oxidatively-modified proteins and their functions.

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Peroxynitrite is a major trigger of cardiomyocyte apoptosis in vitro and in vivo

Cited by 131 publications

References 55 publications

Role of superoxide, nitric oxide, and peroxynitrite in doxorubicin-induced cell death in vivo and in vitro

Role of superoxide, nitric oxide, and peroxynitrite in doxorubicin-induced cell death in vivo and in vitro

Neutral sphingomyelinase inhibition participates to the benefits of N-acetylcysteine treatment in post-myocardial infarction failing heart rats

Oxidative Inactivation of Key Mitochondrial Proteins Leads to Dysfunction and Injury in Hepatic Ischemia Reperfusion

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