Does cyclosporin A generate free radicals?

Buetler, Timo M.; Cottet-Maire, Florence; Krauskopf, Alexandra; Rüegg, Urs T.

doi:10.1016/s0165-6147(00)01508-x

Cited by 40 publications

(30 citation statements)

References 19 publications

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“…15 Our data, for the first time, indicate that not only CsA, but also the more potent calcineurin inhibitor FK506, increase endothelial NAD(P)H oxidase activity, as demonstrated by use of the highly specific inhibitor of NAD(P)H oxidase gp91ds-tat and direct assessment of the enzyme activity. Although the signal pathways underlying these processes were not the 05 vs control).…”

Section: Discussionmentioning

confidence: 53%

“…10 It has been shown that the calcineurin inhibitors cyclosporine A (CsA) and tacrolimus (FK506), which cannot prevent CAV, 5,11 can induce endothelial dysfunction and hypertension, 12,13 which has been explained by an increase in vascular reactive oxygen species (ROS) formation. 14, 15 In contrast to this, the inhibitor of inosine monophosphate dehydrogenase (IMPDH), mycophenolate mofetil, or its active metabolite, mycophenolate acid (MPA), have been associated with positive effects on atherosclerosis or hypertension in animal models. 16 -18 Considering the development and progression of CAV, observations of increased ROS formation caused by immunosuppressive drugs may be of high importance, because the endothelial function can be (at least in nontransplanted patients) profoundly altered by an increased cellular oxidative stress.…”

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confidence: 99%

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Mycophenolate Acid Inhibits Endothelial NAD(P)H Oxidase Activity and Superoxide Formation by a Rac1-Dependent Mechanism

Krötz

Keller²,

Derflinger³

et al. 2007

Hypertension

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Abstract-Endothelial dysfunction precedes hypertension and atherosclerosis and predicts cardiac allograft vasculopathy and death in heart transplant recipients. Endothelial overproduction of reactive oxygen species, such as superoxide anions produced by NAD(P)H oxidase, induces endothelial dysfunction. Because immunosuppressive drugs have been associated with increased reactive oxygen species production and endothelial dysfunction, we sought to elucidate the underlying mechanisms. Reactive oxygen species, release of superoxide anions, and NAD(P)H oxidase activity were studied in human umbilical vein endothelial cells and in polymorphonuclear neutrophils. Gp91ds-tat was used to specifically block NAD(P)H oxidase. Transcriptional activation of different subunits of NAD(P)H oxidase was assessed by real-time RT-PCR. Rac1 subunit translocation and activation were studied by membrane fractionation and pull-down assays. Calcineurin inhibitors significantly increased endothelial superoxide anions production because of NAD(P)H oxidase, whereas mycophenolate acid (MPA) blocked it. MPA also attenuated the respiratory burst induced by neutrophil NAD(P)H oxidase. Because transcriptional activation of NAD(P)H oxidase was not affected, but addition of guanosine restored endothelial superoxide anions formation after MPA treatment, we speculate that the inhibitory effect of MPA was mediated by depletion of cellular guanosine triphosphate content. This prevented activation of Rac1 and, thus, of endothelial NAD(P)H oxidase. Because all heart transplant recipients are at risk for cardiac allograft vasculopathy development, these differential effects of immunosuppressants on endothelial oxidative stress should be considered in the choice of immunosuppressive drugs.

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Section: Discussionmentioning

confidence: 53%

mentioning

confidence: 99%

Mycophenolate Acid Inhibits Endothelial NAD(P)H Oxidase Activity and Superoxide Formation by a Rac1-Dependent Mechanism

Krötz

Keller²,

Derflinger³

et al. 2007

Hypertension

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show abstract

Section: Introductionmentioning

confidence: 99%

“…1,2 However, various organ toxicities-nephrotoxicity, cardiotoxicity, and hepatotoxicity-are its most important side effects, which restrict its long-term use. [1][2][3] There are many hypotheses to explain CsA-associated side effects. These hypotheses list the formation of free oxygen radicals, lipid peroxidation, cytochrome P450 system induction, increase in intracellular calcium, increase in vasoconstrictor eicosanoid synthesis, and apoptosis.…”

Section: Introductionmentioning

confidence: 99%

“…These hypotheses list the formation of free oxygen radicals, lipid peroxidation, cytochrome P450 system induction, increase in intracellular calcium, increase in vasoconstrictor eicosanoid synthesis, and apoptosis. 1,[4][5][6] Free oxygen radical damage is the most frequently mentioned mechanism in the pathogenesis of CsAassociated organ toxicities. 1 Previously conducted studies have shown that it causes oxidative damage in the kidneys 1 and liver 7 and eventually an increase in lipid peroxidation.…”

Section: Introductionmentioning

confidence: 99%

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Antiapoptotic and Antioxidant Effects of GSPE in Preventing Cyclosporine A-Induced Cardiotoxicity

et al. 2012

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Objectives: Cyclosporine A (CsA) is an immunosuppressive drug, but cardiotoxicity is one of its side effects. Free oxygen radical damage and apoptosis are considered to be responsible for CsA-induced cardiotoxicity. Grape seed proanthocyanidin extract (GSPE) displays antioxidant and antiapoptotic activities. Therefore, we aimed to evaluate the effect of GSPE on CsA-induced cardiotoxicity. Materials and methods: Twenty-four rats were divided into four groups, with six rats in each group. CsA-induced nephropathy was induced by administration of 25 mg/kg CsA. The experiment was discontinued on day 21, and total oxidant system (TOS), total antioxidant system (TAS), oxidative stress index (OSI), and malondialdehyde (MDA) were measured in order to evaluate oxidative damage to the heart tissue. In addition to cardiac histopathology, transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL) was performed to determine apoptosis. Results: The CsA group showed a significant increase in TOS, OSI, MDA, cardiac histopathological score, and apoptotic index (AI); in the CsA + GSPE group, OSI, MDA, cardiac histopathological score, and AI decreased significantly, and TAS levels showed a significant increase. Conclusion: In this study, we demonstrated for the first time in the literature that GSPE prevents CsA cardiotoxicity and that this effect can be achieved by antiapoptotic and antioxidant activities

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Potential role of circular RNA in cyclosporin A‐induced cardiotoxicity in rats

Zhang

Fan

et al. 2021

J of Applied Toxicology

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Cyclosporin A (CsA) is a well-known and effective drug that is commonly used in autoimmune diseases and allotransplantation. However, kidney toxicity and cardiotoxicity limit its use. Circular RNAs (circRNAs) play a crucial role in disease, especially cardiovascular disease. We aimed to explore the circRNA expression profiles and potential mechanisms during CsA-induced cardiotoxicity. Sixty male adult Wistar rats were randomly divided into two groups. The CsA group was injected with CsA (15 mg/kg/day body weight) intraperitoneally (ip) for 2 weeks, whereas the control group was injected ip with the same volume of olive oil. We assessed CsA-induced cardiotoxicity by light microscopy, transferase-mediated dUTP nick-end labeling (TUNEL) staining, and electron microscopy. Microarray analysis was used to detect the expression profiles of circRNAs deregulated in the heart during CsA-induced cardiotoxicity. We confirmed the changes in circRNAs by quantitative PCR. Moreover, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses of the microarray data were performed. A conventional dose of CsA induced cardiotoxicity in rats. We identified 67 upregulated and 37 downregulated circRNAs compared with those in the control group. Six of 12 circRNAs were successfully verified by quantitative real-time polymerase chain reaction (qRT-PCR). GO analyses of the differentially expressed circRNAs indicated that these molecules might play important roles in CsA-induced cardiotoxicity. KEGG pathway analyses showed that the differentially expressed circRNAs in CsA-induced cardiotoxicity may be related to autophagy or the Hippo signaling pathway. We identified differential circRNA expression patterns and provided more insight into the mechanism of CsA-induced cardiotoxicity. CircRNAs may serve as potential biomarkers or therapeutic targets of CsA-mediated cardiotoxicity in the future.

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Does cyclosporin A generate free radicals?

Cited by 40 publications

References 19 publications

Mycophenolate Acid Inhibits Endothelial NAD(P)H Oxidase Activity and Superoxide Formation by a Rac1-Dependent Mechanism

Mycophenolate Acid Inhibits Endothelial NAD(P)H Oxidase Activity and Superoxide Formation by a Rac1-Dependent Mechanism

Antiapoptotic and Antioxidant Effects of GSPE in Preventing Cyclosporine A-Induced Cardiotoxicity

Potential role of circular RNA in cyclosporin A‐induced cardiotoxicity in rats

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