Cyclosporin A Protected Cardiomyocytes Against Oxidative Stress Injury by Inhibition of NF- κ B Signaling Pathway

Abstract

Purpose

This study aims to investigate the effects and the molecular mechanism of cyclosporin A (CsA) against oxidative stress injury in cultured neonatal rat cardiomyocytes.

Methods

Bax/Bcl-2, cl-casp-9/casp-9, cl-casp-3/casp-3, and iNOS/β-actin ratios and p-IκB and IκB levels were analyzed by western blot. IL-1β and TNF-α levels were analyzed by ELISA.

Results

CsA effectively improved the cell viability and reduced the extracellular lactate dehydrogenase release in cardiomyocytes after H₂O₂-induced oxidative damage. CsA significantly increased the superoxide dismutase activity, glutathione production, and catalase activity but decreased the malonaldehyde level. CsA treatment considerably reduced the H₂O₂-induced intracellular generation of reactive oxygen species, mitochondrial dysfunction, and release of cytochrome c. CsA could act against H₂O₂-induced ATP reduction, TCA cycle enzymes, mitochondrial complex I enzyme, and complex V enzyme in cardiomyocytes. CsA significantly decreased the Bax/Bcl-2 ratio, cl-casp-9/casp-9, and cl-casp-3/casp-3 in a concentration-dependent manner. CsA also remarkably reduced the cleaved PARP level and DNA fragmentation. NF-κB was closely related to oxidative stress injury. CsA inhibited NF-κB activation, thereby preventing the upregulation of IL-1β, TNF-α, iNOS, and intracellular NO release.

Conclusions

CsA protected cardiomyocytes against H₂O₂-induced cell injury. Hence, CsA may be developed as a candidate drug to prevent or treat myocardial ischemia reperfusion injury.

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