OBJECTIVE
To understand the role of Nuclear Factor-κB (NF-κB) in the regulation of mitochondrial permeability transition pore opening (mPTP) and cardiac cell death during doxorubicin cardiotoxicity.
METHODS AND RESULTS
Cardiac myocytes expressing a kinase defective form of IKKβ (IKKK-M) the principle IKK required for NF-κB activation, displayed impaired NF-κB gene activity. Defects in NF-κB signaling coincided with an increase in mitochondrial permeability transition pore (mPTP) opening and cell death. Interestingly, mPTP opening and cell death observed in the NF-κB defective cardiomyocytes was supressed by inhibition of mPTP modulator CypD, with cyclosporin A (CSA) or by siRNA knock down (CypDsiRNA), suggesting a link between mPTP regulation and NF-κB signaling. Interestingly, we observed a dramatic reduction in NF-κB signaling in cardiac myocytes treated with doxorubicin Dox (18 Hrs), coupled with mitochondrial dysfunction that included impaired calcium signaling, oxidative metabolism and mPTP. Inhibition of CyPD suppressed Dox- induced cell death of cardiac myocytes. Finally restoration of NF-κB signaling in cardiac myocytes treated with Dox by IKKβ, active kinase, suppressed mitochondrial calcium overload, mitochondrial perturbations, respiration and cell death.
CONCLUSION The data provides the first evidence that impaired NF-κB signaling predisposes in cardiac myocytes treated with DOX to necrotic cell death through a mechanism that impinges upon mPTP