Enhanced gene expression of myocardial matrix metalloproteinases 2 and 9 after acute treatment with doxorubicin in mice

Kizaki, Keiichiro; Itô, Ryôichi; Okada, Muneyoshi; Yoshioka, Kazuki; Uchide, Tsuyoshi; Temma, Kyosuke; Mutoh, Ken-ichiro; Uechi, Masami; Hara, Yukio

doi:10.1016/j.phrs.2006.01.001

Cited by 45 publications

(46 citation statements)

References 35 publications

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“…(4,5,13). DOX via increased generation of reactive oxygen and nitrogen species also leads to activation of MMP enzymes (31), which in turn promotes pathological remodeling (4,14,32,33). CBD attenuated DOX-induced myocardial lipid peroxidation and the decline in antioxidant glutathione level and in the activity of glutathione peroxidase, which could be the consequence of attenuated formation or enhanced inactivation of reactive oxygen and nitrogen species.…”

Section: Discussionmentioning

confidence: 99%

Cannabidiol Protects against Doxorubicin-Induced Cardiomyopathy by Modulating Mitochondrial Function and Biogenesis

Hao

Mukhopadhyay

Cao

et al. 2015

Mol Med

136

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Doxorubicin (DOX) is a widely used, potent chemotherapeutic agent; however, its clinical application is limited because of its dose-dependent cardiotoxicity. DOX's cardiotoxicity involves increased oxidative/nitrative stress, impaired mitochondrial function in cardiomyocytes/endothelial cells and cell death. Cannabidiol (CBD) is a nonpsychotropic constituent of marijuana, which is well tolerated in humans, with antioxidant, antiinflammatory and recently discovered antitumor properties. We aimed to explore the effects of CBD in a well-established mouse model of DOX-induced cardiomyopathy. DOX-induced cardiomyopathy was characterized by increased myocardial injury (elevated serum creatine kinase and lactate dehydrogenase levels), myocardial oxidative and nitrative stress (decreased total glutathione content and glutathione peroxidase 1 activity, increased lipid peroxidation, 3-nitrotyrosine formation and expression of inducible nitric oxide synthase mRNA), myocardial cell death (apoptotic and poly[ADP]-ribose polymerase 1 [PARP]-dependent) and cardiac dysfunction (decline in ejection fraction and left ventricular fractional shortening). DOX also impaired myocardial mitochondrial biogenesis (decreased mitochondrial copy number, mRNA expression of peroxisome proliferator-activated receptor γ coactivator 1-alpha, peroxisome proliferator-activated receptor alpha, estrogen-related receptor alpha), reduced mitochondrial function (attenuated complex I and II activities) and decreased myocardial expression of uncoupling protein 2 and 3 and medium-chain acyl-CoA dehydrogenase mRNA. Treatment with CBD markedly improved DOX-induced cardiac dysfunction, oxidative/nitrative stress and cell death. CBD also enhanced the DOX-induced impaired cardiac mitochondrial function and biogenesis. These data suggest that CBD may represent a novel cardioprotective strategy against DOX-induced cardiotoxicity, and the above-described effects on mitochondrial function and biogenesis may contribute to its beneficial properties described in numerous other models of tissue injury.

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Section: Discussionmentioning

confidence: 99%

Cannabidiol Protects against Doxorubicin-Induced Cardiomyopathy by Modulating Mitochondrial Function and Biogenesis

Hao

Mukhopadhyay

Cao

et al. 2015

Mol Med

136

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“…This is further supported by the findings that PSs also attenuate the activation of known effector pathways for myocardial injury triggered by peroxynitrite (e.g., the activation of the nuclear enzyme PARP-1 and MMPs) in our DOX-induced heart failure model. Pharmacological inhibition of PARP or genetic deletion of PARP-1 is known to be protective in mouse models of DOX-induced cardiomyopathy/heart failure (44,45), whereas the precise role and consequences of MMP activation (3,19,58) deserve additional exploration.…”

Section: Discussionmentioning

confidence: 99%

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

329

270

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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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“…This could contribute to the mechanism of complications of anti-cancer therapy such as clinically documented anthracycline-induced nephrotoxicity or retroperitoneal fibrosis induced by ionizing radiation. Moreover, some drugs, such as anthracyclines, may favor ECM remodeling by stimulating MMP production, such as documented for MMP-2 or MMP-9 in cardiac myocytes (Kizaki et al, 2006). This could explain the loss of heart collagen mass in doxorubicintreated animals, one of the features of anthracyclininduced cardiotoxicity.…”

Section: Impact Of Anti-cancer Agents On Ecm Remodelingmentioning

confidence: 99%

Influence of stress on extracellular matrix and integrin biology

et al. 2011

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Enhanced gene expression of myocardial matrix metalloproteinases 2 and 9 after acute treatment with doxorubicin in mice

Cited by 45 publications

References 35 publications

Cannabidiol Protects against Doxorubicin-Induced Cardiomyopathy by Modulating Mitochondrial Function and Biogenesis

Cannabidiol Protects against Doxorubicin-Induced Cardiomyopathy by Modulating Mitochondrial Function and Biogenesis

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

Influence of stress on extracellular matrix and integrin biology

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