title: Arsenic-induced interstitial myocardial fibrosis reveals a new insight into drug-induced long QT syndrome.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pharmacology, Harbin Medical University, Xuefu Road 194, Harbin, Heilongjiang 150081, PR China.
authors.forename: Wenfeng
authors.initials: W
authors.lastname: Chu
authors.forename: Cui
authors.initials: C
authors.lastname: Li
authors.forename: Xuefeng
authors.initials: X
authors.lastname: Qu
authors.forename: Dan
authors.initials: D
authors.lastname: Zhao
authors.forename: Xuelian
authors.initials: X
authors.lastname: Wang
authors.forename: Xiangru
authors.initials: X
authors.lastname: Yu
authors.forename: Fulai
authors.initials: F
authors.lastname: Cai
authors.forename: Haihai
authors.initials: H
authors.lastname: Liang
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhang
authors.forename: Xin
authors.initials: X
authors.lastname: Zhao
authors.forename: Baoxin
authors.initials: B
authors.lastname: Li
authors.forename: Guofen
authors.initials: G
authors.lastname: Qiao
authors.forename: Deli
authors.initials: D
authors.lastname: Dong
authors.forename: Yanjie
authors.initials: Y
authors.lastname: Lu
authors.forename: Zhimin
authors.initials: Z
authors.lastname: Du
authors.forename: Baofeng
authors.initials: B
authors.lastname: Yang
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000970:Antineoplastic Agents / Q000009:adverse effects*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000009:adverse effects*; D003094:Collagen / Q000378:metabolism; D015536:Down-Regulation; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism*; D005355:Fibrosis; D006168:Guinea Pigs; D057809:HEK293 Cells; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D009206:Myocardium / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism; D010087:Oxides / Q000009:adverse effects*; D024661:Potassium Channels, Inwardly Rectifying / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D001152:Arsenicals; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; C489461:Kir2.1 channel; D010087:Oxides; D024661:Potassium Channels, Inwardly Rectifying; D053773:Transforming Growth Factor beta1; D003094:Collagen; D000077237:Arsenic Trioxide