Direct, pleiotropic protective effect of cyclosporin A against simulated ischemia-induced injury in isolated cardiomyocytes

Bés, Sandrine; Vandroux, David; Tissier, Cindy; Devillard, L.; Brochot, Amandine; Tatou, Etienne; Duvillard, Laurence; Rochette, Luc; Athias, Pierre

doi:10.1016/j.ejphar.2005.02.016

Cited by 14 publications

(3 citation statements)

References 43 publications

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“…The prolongation of MAPD in the early phase of reperfusion, which was reported previously by Bes et al and Ducroq et al in vitro [6], [7], was confirmed in our study in vivo . The careful use of controls in this study also demonstrated that blockade of I Ks by L-768,673 prolonged both the MAPD90 and MAPD60 in the interval between R30and R90, which provided evidence of the increased contribution of the I Ks current in repolarization currents.…”

Section: Discussionsupporting

confidence: 92%

“…For example, when cardiac ischemia was induced, the contribution of adenosine triphosphate sensitive potassium current (I KATP ) to repolarization was increased, while those of IKr and IK1 were lessened in comparison, which led in turn to a shortening of the APD [5]. The shortening of the APD induced by ischemia is gradually restored by reperfusion, however a temporary prolongation of APD during early reperfusion was observed by Ducroq et al and Bes et al in an in vitro model of simulated ischemia and reperfusion in isolated cardiomyocytes [6], [7]. This phenomenon, which directly involved repolarization ion current function, has not yet been well explained.…”

Section: Introductionmentioning

confidence: 98%

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IKs Protects from Ventricular Arrhythmia during Cardiac Ischemia and Reperfusion in Rabbits by Preserving the Repolarization Reserve

et al. 2012

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IntroductionThe function of the repolarization reserve in the prevention of ventricular arrhythmias during cardiac ischemia/reperfusion and the impact of ischemia on slowly activated delayed rectifier potassium current (IKs) channel subunit expression are not well understood.Methods and ResultsThe responses of monophasic action potential duration (MAPD) prolongation and triangulation were investigated following an L-768,673-induced blockade of IKs with or without ischemia/reperfusion in a rabbit model of left circumflex coronary artery occlusion/reperfusion. Ischemia/reperfusion and IKs blockade were found to significantly induce MAPD90 prolongation and increase triangulation at the epicardial zone at 45 min, 60 min, and 75 min after reperfusion, accompanied with an increase in premature ventricular beats (PVBs) during the same period. Additionally, IKs channel subunit expression was examined following transient ischemia or permanent infarction and changes in monophasic action potential (MAP) waveforms challenged by β-adrenergic stimulation were evaluated using a rabbit model of transient or chronic cardiac ischemia. The epicardial MAP in the peri-infarct zone of hearts subjected to infarction for 2 days exhibited increased triangulation under adrenergic stimulation. KCNQ1 protein, the α subunit of the IKs channel, was downregulated in the same group. Both findings were consistent with an increased incidence of PVBs.ConclusionBlockade of IKs caused MAP triangulation, which precipitated ventricular arrhythmias. Chronic ischemia increased the incidence of ventricular arrhythmias under adrenergic stimulation and was associated with increased MAP triangulation of the peri-infarct zone. Downregulation of KCNQ1 protein may be the underlying cause of these changes.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 98%

IKs Protects from Ventricular Arrhythmia during Cardiac Ischemia and Reperfusion in Rabbits by Preserving the Repolarization Reserve

et al. 2012

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“…CsA‐induced cardiotoxicity is controversial. Some studies have indicated that CsA can ameliorate heart failure (Sharov et al, 2007 ) and cardiac hypertrophy (Schreiner et al, 2004 ) and protect the heart from ischemia–reperfusion injury (Bes et al, 2005 ). However, our previous report and other studies have found that CsA results in myocardial structural damage and increased cardiomyocyte apoptosis (Tang et al, 2011 ; Zhao et al, 2011 ) and myocardial fibrosis in rats (Rezzani et al, 2003 ).…”

Section: Introductionmentioning

confidence: 99%

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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Cyclosporin A induces apoptosis in H9c2 cardiomyoblast cells through calcium-sensing receptor-mediated activation of the ERK MAPK and p38 MAPK pathways

Chi

Zhu

et al. 2012

Mol Cell Biochem

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The cardiotoxicity of cyclosporine A (CsA) limits its clinical application in extensive and long-term therapies. Our group has shown that CsA induces myocardium cell apoptosis in vivo and increases calcium-sensing receptor (CaSR) expression. However, its molecular mechanism remains unknown. The purpose of this study was to determine whether CaSR plays an essential role in CsA-induced apoptosis in H9c2 cells and to investigate the role of the mitogen-activated protein kinase (MAPK) signaling cascade in this process. H9c2 cells were treated with CsA in a dose-dependent manner, and decreased Bcl-2 expression, increased Bax expression, and caspase-3 activation were observed. In a time-dependent manner, CsA increased CaSR expression, activated the extracellularly regulated kinase (ERK) and p38 MAPK pathways, and inactivated the c-Jun N-terminal kinase (JNK) MAPK signaling pathway. When H9c2 cardiomyoblast cells pretreated with gadolinium chloride (GdCl(3)), a CaSR activator, were treated with CsA, decreased phosphorylation of ERK1/2, increased phosphorylation of p38, decreased Bcl-2 expression, increased Bax expression, and activated caspase-3 were observed. Cells pretreated with the CaSR inhibitor NPS2390 inhibited this process. Furthermore, the MEK1/2 inhibitor U0126 and the p38 MAPK inhibitor SB203580 markedly blocked the effect of CsA on cell apoptosis, apoptotic-related protein expression, and caspase-3 activation. These findings showed that CsA induced apoptosis in H9c2 cells in vitro, and CaSR mediated the degradation of ERK MAPK and the upregulation of the p38 MAPK pathway involved in CsA-induced H9c2 cardiomyoblast cell apoptosis.

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Direct, pleiotropic protective effect of cyclosporin A against simulated ischemia-induced injury in isolated cardiomyocytes

Cited by 14 publications

References 43 publications

IKs Protects from Ventricular Arrhythmia during Cardiac Ischemia and Reperfusion in Rabbits by Preserving the Repolarization Reserve

IKs Protects from Ventricular Arrhythmia during Cardiac Ischemia and Reperfusion in Rabbits by Preserving the Repolarization Reserve

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

Cyclosporin A induces apoptosis in H9c2 cardiomyoblast cells through calcium-sensing receptor-mediated activation of the ERK MAPK and p38 MAPK pathways

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