title: Arsenic trioxide induces cardiac fibroblast apoptosis in vitro and in vivo by up-regulating TGF-β1 expression.
abstract: Arsenic trioxide (As2O3; ATO) is clinically effective in treating acute promyelocytic leukemia (APL); however, it frequently causes cardiotoxic effects. This study was designed to investigate whether ATO could induce apoptosis of cardiac fibroblasts (CFs) that play very important roles in maintaining the structure integrity and function of the heart. Cardiac fibroblasts from guinea pigs administered with ATO (1mg/kgbw) were used to test the pro-apoptotic role of ATO in vivo. The current study demonstrated that ATO induced morphological characteristics of apoptosis and Caspase-3 activation in CFs of guinea pigs along with a significant up-regulation in TGF-β1 protein expression, Bax/Bcl-2 ratio and ERK1/2 phosphorylation. In vitro MTT assay showed that ATO remarkably reduced the viability of cultured cardiac fibroblasts (NRCFs) from neonatal rat in a concentration- and time-dependent manner. Consistent with the notions in vivo, ATO significantly induced the apoptosis in NRCFs, dramatically up-regulated TGF-β1 protein level and Bax/Bcl-2 ratio in a time-dependent fashion and activated Caspase-3 and ERK1/2. Finally, pretreatment with LY364947, an inhibitor of TGF-β signaling could apparently reverse these changes. We therefore conclude that TGF-β is functionally linked to ERK1/2 and that TGF-β signaling is responsible for ATO-induced CFs apoptosis, which provides a novel mechanism of ATO related cardiac toxicology.
authors.affiliation: Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical University, Harbin, Heilongjiang 150081, China.
authors.forename: Cui
authors.initials: C
authors.lastname: Li
authors.forename: Xuefeng
authors.initials: X
authors.lastname: Qu
authors.forename: Wenxiao
authors.initials: W
authors.lastname: Xu
authors.forename: Ning
authors.initials: N
authors.lastname: Qu
authors.forename: Liu
authors.initials: L
authors.lastname: Mei
authors.forename: Yu
authors.initials: Y
authors.lastname: Liu
authors.forename: Xuelian
authors.initials: X
authors.lastname: Wang
authors.forename: Xiangru
authors.initials: X
authors.lastname: Yu
authors.forename: Zengyan
authors.initials: Z
authors.lastname: Liu
authors.forename: Dan
authors.initials: D
authors.lastname: Nie
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.forename: Jinglong
authors.initials: J
authors.lastname: Yan
authors.forename: Baofeng
authors.initials: B
authors.lastname: Yang
authors.forename: Yanjie
authors.initials: Y
authors.lastname: Lu
authors.forename: Wenfeng
authors.initials: W
authors.lastname: Chu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D002478:Cells, Cultured; D005347:Fibroblasts / Q000187:drug effects*; D015870:Gene Expression / Q000187:drug effects; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects*; D008297:Male; D008854:Microscopy, Electron; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D010087:Oxides / Q000494:pharmacology*; D051381:Rats; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D001152:Arsenicals; D010087:Oxides; D053773:Transforming Growth Factor beta1; D053148:Caspase 3; D000077237:Arsenic Trioxide