Aims: Arsenic trioxide (ATO), an effective therapeutic agent for acute promyelocytic leukaemia, can cause sudden cardiac death due to long QT syndrome (LQTS). The present study was designed to determine whether ATO could induce cardiac fibrosis and explore whether cardiac fibroblasts (CFs) are involved in the development of LQTS by ATO.
Methods and results: ATO treatment of guinea pigs caused substantial interstitial myocardial fibrosis and LQTS, which was accompanied by an increase in transforming growth factor β1(TGF-β1) secretion and a decrease in ether-à-go-go-related gene (HERG) and inward rectifying potassium channel (I(K1)) subunit Kir2.1 protein levels. ATO promoted collagen production and TGF-β1 expression and secretion in cultured CFs. Whole-cell patch clamp and western blotting showed that treatment with TGF-β1 markedly reduced HERG and I(K1) current densities and downregulated HERG and Kir2.1 protein expression in HEK293 cells stably transfected with the human recombinant HERG channel and in cardiomyocytes (CMs). These changes were completely reversed by treatment with the protein kinase A (PKA) antagonist, H89. CM and CF co-cultures showed that ATO significantly increased TGF-β1 levels in the culture medium, whereas markedly reduced HERG and Kir2.1 protein levels were observed in CMs compared with ATO-treated CMs not co-cultured with CFs. Finally, in vivo administration of LY364947, a pharmacological antagonist of TGF-β signalling, dramatically prevented interstitial fibrosis and LQTS and abolished aberrant expression of TGF-β1, HERG, and Kir2.1 in ATO-treated guinea pigs.
Conclusion: ATO-induced TGF-β1 secretion from CFs aggravates QT prolongation, suggesting that modulation of TGF-β signalling may provide a novel strategy for the treatment of drug-induced LQTS.