Cyclosporine A regulate oxidative stress-induced apoptosis in cardiomyocytes: Mechanisms via ROS generation, iNOS and Hsp70

Huei Wen Chen, Chiang Ting Chien, Sung Liang Yu, Yuan Teh Lee, Wen Jone Chen

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Abstract

1. Previous study suggested that cyclosporine A (CsA) could partially reduce ischaemia/reperfusion-induced injury in isolated heart, but the mechanism was still unclear. In this study, the possible mechanisms of cyclosporine A in regulating oxidative stress-induced cardiomyocyte apoptosis were examined. 2. Morphological (cell shrinkage, apoptotic body formation, and DNA fragmentation) and biochemical (annexin-V staining for exposed phosphatidylserine residues) evidences showed that both hydrogen peroxide (H 2O 2) and hypoxia/reoxygenation could induce apoptotic change in the embryonal rat heart myoblast-derived cells (H9c2). These effects were inhibited by pre-treatment with CsA at concentration of 0.01-1.0 μM for 24 h, but were increased with 10.0 μM CsA. 3. While examining the mechanisms of CsA in protecting cardiomyocyte apoptosis, we found that the collapse of mitochondria membrane potential (Δψm) induced by oxidative stress was partially reversed by CsA (0.01-1.0 μM). 4. Compared to the control, CSA at the concentration of 0.1 and 10.0 μM significantly increased the level of intracellular reactive oxygen species (ROS) to 117.2±12.4% and 234.4±9.3%, respectively. Co-incubating with the antioxidant, ascorbic acid (10.0 μM), could partially reduce the protective effect of CsA (0.01-1.0 μM) and the toxic effect of 10.0 μM CsA. 5. Pre-treatment with CsA at concentration of 0.01-1.0 μM for 24 h produced up-regulation of heat shock protein 70 (Hsp 70), inducible nitric oxide synthase (iNOS) and also induced NO production, indicating that these factors might be associated with the cell protective effects of CsA. 6. These results suggest that CsA could protect the oxidative stress-induced cardiomyocyte apoptosis not only by preventing the loss of Δψm in mitochondria, but also through ROS generation, Hsp70, and iNOS up-regulation.

Original languageEnglish
Pages (from-to)771-781
Number of pages11
JournalBritish Journal of Pharmacology
Volume137
Issue number6
DOIs
Publication statusPublished - 2002 Nov 1

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Keywords

  • Cardiomyocytes
  • Cyclosporine A
  • Free radicals
  • Membrane potential
  • Mitochondria

ASJC Scopus subject areas

  • Pharmacology

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