Arsenic trioxide induces cardiac fibroblast apoptosis in vitro and in vivo by up-regulating TGF-¦Â1 expression

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• 作者：Cui Li^a ; ¹ ; Xuefeng Qu^a ; ¹ ; Wenxiao Xu^b ; ¹ ; Ning Qu^c ; Liu Mei^a ; Yu Liu^a ; Xuelian Wang^a ; Xiangru Yu^a ; Zengyan Liu^a ; Dan Nie^a ; Yang Liu^a ; Jinglong Yan^b ; Baofeng Yang^a ; Yanjie Lu^a ; ^{yjlu86@yahoo.com} ; Wenfeng Chu^a ; ^{chu.wenfeng@gmail.com}
• 关键词：ATO ; arsenic trioxide ; APL ; acute promyelocytic leukemia ; CFs ; cardiac fibroblasts ; NRCFs ; neonatal rat cardiac fibroblasts ; TGF-¦Â1 ; transforming growth factor-¦Â1 ; LY364947 ; TGF-¦Â signaling inhibitor ; its chemical formula is 4-[3-(2-pyridinyl)-1H-pyraz
• 刊名：Toxicology Letters
• 出版年：2013
• 出版时间：7 June, 2013
• 年：2013
• 卷：219
• 期：3
• 页码：223-230
• 全文大小：1802 K

文摘

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 (1 mg/kg bw) 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-¦Â1 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-¦Â1 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-¦Â signaling could apparently reverse these changes. We therefore conclude that TGF-¦Â is functionally linked to ERK1/2 and that TGF-¦Â signaling is responsible for ATO-induced CFs apoptosis, which provides a novel mechanism of ATO related cardiac toxicology.