Chronic Anthracycline Cardiotoxicity: Molecular and Functional Analysis with Focus on Nuclear Factor Erythroid 2-Related Factor 2 and Mitochondrial Biogenesis Pathways

Jirkovský, Eduard; Popelová, Olga; Kriváková-Stanková, P; Vávrová, Anna; Hroch, Miloš; Hašková, Pavlína; Brcakova-Dolezelova, Eva; Mičuda, Stanislav; Adamcová, Michaela; Šimůnek, Tomáš; Červinková, Z; Gersl,; Štěrba, Martin

doi:10.1124/jpet.112.198358

Cited by 50 publications

(35 citation statements)

References 49 publications

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“…Issan et al (18) observed increased protein expression of HMOX1 after short anoxic (120 min, 100% argon exposure) stimulus, and overexpression of HMOX1 attenuated cardiomyocyte damage caused by an anoxic insult. Moreover, HMOX is often increased in the defense to cardiotoxic stimuli (23). Another iron-dependent antioxidant ACO1 displayed elevated mRNA levels under both protective regimens in our study.…”

Section: Discussionmentioning

confidence: 50%

Cardioprotective and nonprotective regimens of chronic hypoxia diversely affect the myocardial antioxidant systems

Kasparova

Neckář

Dabrowská

et al. 2015

Physiological Genomics

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Cardioprotective and nonprotective regimens of chronic hypoxia diversely affect the myocardial antioxidant systems. Physiol Genomics 47: 612-620, 2015. First published October 13, 2015; doi:10.1152/physiolgenomics.00058.2015.-It has been documented that adaptation to hypoxia increases myocardial tolerance to ischemia-reperfusion (I/R) injury depending on the regimen of adaptation. Reactive oxygen species (ROS) formed during hypoxia play an important role in the induction of protective cardiac phenotype. On the other hand, the excess of ROS can contribute to tissue damage caused by I/R. Here we investigated the relationship between myocardial tolerance to I/R injury and transcription activity of major antioxidant genes, transcription factors, and oxidative stress in three different regimens of chronic hypoxia. Adult male Wistar rats were exposed to continuous normobaric hypoxia (FIO 2 0.1) either continuously (CNH) or intermittently for 8 h/day (INH8) or 23 h/day (INH23) for 3 wk period. A control group was kept in room air. Myocardial infarct size was assessed in anesthetized open-chest animals subjected to 20 min coronary artery occlusion and 3 h reperfusion. Levels of mRNA transcripts and the ratio of reduced and oxidized glutathione (GSH/GSSG) were analyzed by real-time RT-PCR and by liquid chromatography, respectively. Whereas CNH as well as INH8 decreased infarct size, 1 h daily reoxygenation (INH23) abolished the cardioprotective effect and decreased GSH/GSSG ratio. The majority of mRNAs of antioxidant genes related to mitochondrial antioxidant defense (manganese superoxide dismutase, glutathione reductase, thioredoxin/thioredoxin reductase, and peroxiredoxin 2) were upregulated in both cardioprotective regimens (CNH, INH8). In contrast, INH23 increased only PRX5, which was not sufficient to induce the cardioprotective phenotype. Our results suggest that the increased mitochondrial antioxidant defense plays an important role in cardioprotection afforded by chronic hypoxia. adaptation to hypoxia; cardioprotection; ischemia-reperfusion injury; oxidative stress; antioxidant defense ADAPTATION TO CHRONIC HYPOXIA may improve cardiac tolerance to acute ischemia-reperfusion (I/R) injury under certain conditions. Whereas chronic continuous hypoxia induces a protective cardiac phenotype, a brief daily interruption of hypoxic adaptation for 1 h eliminates the protective effect (31). Tissue damage caused by I/R insult is tightly related to the excess of reactive oxygen species (ROS), but the exact molecular mechanism underlying these adverse effects is still not fully elucidated. Intracellular ROS initiate a sequence of oxidation reactions that can seriously damage cell structures. ROS differ in their reactivity, as well as in mechanisms and sites of their production. These harmful species can be eliminated by specific scavengers. If production of ROS exceeds the capacity limit of antioxidant systems or if the systemic capacity is insufficient, the level of ROS in individual cell compartments increases and generates ...

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Section: Discussionmentioning

confidence: 50%

Cardioprotective and nonprotective regimens of chronic hypoxia diversely affect the myocardial antioxidant systems

Kasparova

Neckář

Dabrowská

et al. 2015

Physiological Genomics

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“…40,41 The same was found in daunorubicin-treated male rabbits. 14 In the present study, PGC-1β seemed a relevant target of doxorubicin in males because its downregulation is also observed at the onset of cardiac toxicity. PGC-1β discovered a decade ago, is expressed predominantly in skeletal muscle, heart, brain, and brown adipose tissue.…”

Section: Discussionmentioning

confidence: 95%

“…However, the level and importance of oxidative stress are surely time, species, and concentration dependent leading to different results according to the model of doxorubicin treatment. 4,14,27,28,31,32 Cardiomyocyte loss through various cell death signaling pathways linked to oxidative stress and DNA damage and mitochondrial alterations has been described in doxorubicin cardiotoxicity. 28,33 However, depending on in vitro and in vivo analyses, the results were not always consistent.…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies showed the importance of AMPK in the cardiotoxicity of anthracyclines, but these were conducted only in 12,14 To elucidate whether the sex-dependent doxorubicin cardiotoxicity difference could be linked to AMPK signaling, we analyzed the level of total and phosphorylated AMPK and acetyl-CoA carboxylase, its downstream target. An important decrease of total AMPK (55%), total acetyl-CoA carboxylase (57%), and phosphorylated acetyl-CoA carboxylase (61%) was present in doxorubicin-treated males.…”

Section: Specific Downregulation Of Carbohydrate Utilization Pathway mentioning

confidence: 99%

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Sexual Dimorphism of Doxorubicin-Mediated Cardiotoxicity

Moulin

Piquereau

Matéo

et al. 2015

Circ: Heart Failure

111

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Background— Cardiovascular diseases are the major cause of mortality among both men and women with a lower incidence in women before menopause. The clinical use of doxorubicin, widely used as an antineoplastic agent, is markedly hampered by severe cardiotoxicity. Even if there is a significant sex difference in incidence of cardiovascular disease at the adult stage, it is not known whether a difference in doxorubicin-related cardiotoxicity between men and women also exists. The objective of this work was to explore the cardiac side effects of doxorubicin in adult rats and decipher whether signaling pathways involved in cardiac toxicity differ between sexes. Methods and Results— After 7 weeks of doxorubicin (2 mg/kg per week), males developed major signs of cardiomyopathy with cardiac atrophy, reduced left ventricular ejection fraction and 50% mortality. In contrast, no female died and their left ventricular ejection fraction was only moderately affected. Surprisingly, neither global oxidation levels nor the antioxidant response nor the apoptosis signaling pathways were altered by doxorubicin. However, the level of total adenosine monophosphate–activated protein kinase was severely decreased only in males. Moreover, markers of mitochondrial biogenesis and cardiolipin content were strongly reduced only in males. To analyze the onset of the pathology, maximal oxygen consumption rate of left ventricular permeabilized fibers after 4 weeks of treatment was reduced only in doxorubicin-treated males. Conclusions— Altogether, these results clearly evidence sex differences in doxorubicin toxicity. Cardiac mitochondrial dysfunction and adenosine monophosphate–activated protein kinase seem as critical sites of sex differences in cardiotoxicity as evidenced by significant statistical interactions between sex and treatment effects.

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“…Previous studies have also shown doxorubicin to cause cardiotoxicity through the generation of free radicals [5], stimulation of lipid peroxidation [6] and alteration and disruption of cellular membrane integrity [7]. Arrhythmias, hypotension and depression of the contractile function are some of the acute effects of doxorubicin-induced cardiotoxicity [8], while chronic heart failure and dilative cardiomyopathy are more common and severe in patients who are on long term anthracyclines treatment [9,10]. Large scale clinical trials have shown that doxorubicin induced cardiotoxicity is irreversible and dose dependent [11].…”

Section: Introductionmentioning

confidence: 99%

Attenuation of doxorubicin-induced cardiotoxicity by mdivi-1: A mitochondrial division/mitophagy inhibitor

Gharanei¹,

Hussain²,

Janneh³

et al. 2014

Journal of Pharmacological and Toxicological Methods

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Doxorubicin is one of the most effective anti-cancer agents. However, its use is associated with adverse cardiac effects, including cardiomyopathy and progressive heart failure. Given the multiple beneficial effects of the mitochondrial division inhibitor (mdivi-1) in a variety of pathological conditions including heart failure and ischaemia and reperfusion injury, we investigated the effects of mdivi-1 on doxorubicin-induced cardiac dysfunction in naïve and stressed conditions using Langendorff perfused heart models and a model of oxidative stress was used to assess the effects of drug treatments on the mitochondrial depolarisation and hypercontracture of cardiac myocytes. Western blot analysis was used to measure the levels of p-Akt and p-Erk 1/2 and flow cytometry analysis was used to measure the levels p-Drp1 and p-p53 upon drug treatment. The HL60 leukaemia cell line was used to evaluate the effects of pharmacological inhibition of mitochondrial division on the cytotoxicity of doxorubicin in a cancer cell line. Doxorubicin caused a significant impairment of cardiac function and increased the infarct size to risk ratio in both naïve conditions and during ischaemia/reperfusion injury. Interestingly, co-treatment of doxorubicin with mdivi-1 attenuated these detrimental effects of doxorubicin. Doxorubicin also caused a reduction in the time taken to depolarisation and hypercontracture of cardiac myocytes, which were reversed with mdivi-1. Finally, doxorubicin caused a significant elevation in the levels of signalling proteins p-Akt, p-Erk 1/2, p-Drp1 and p-p53. Co-incubation of mdivi-1 with doxorubicin did not reduce the cytotoxicity of doxorubicin against HL-60 cells. These data suggest that the inhibition of mitochondrial fission protects the heart against doxorubicin-induced cardiac injury and identify mitochondrial fission as a new therapeutic target in ameliorating doxorubicin-induced cardiotoxicity without affecting its anti-cancer properties.

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Chronic Anthracycline Cardiotoxicity: Molecular and Functional Analysis with Focus on Nuclear Factor Erythroid 2-Related Factor 2 and Mitochondrial Biogenesis Pathways

Cited by 50 publications

References 49 publications

Cardioprotective and nonprotective regimens of chronic hypoxia diversely affect the myocardial antioxidant systems

Cardioprotective and nonprotective regimens of chronic hypoxia diversely affect the myocardial antioxidant systems

Sexual Dimorphism of Doxorubicin-Mediated Cardiotoxicity

Attenuation of doxorubicin-induced cardiotoxicity by mdivi-1: A mitochondrial division/mitophagy inhibitor

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