Arsenic trioxide induces cardiac fibroblast apoptosis in vitro and in vivo by up-regulating TGF-beta 1 expression

作者：Li Cui; Qu Xuefeng; Xu Wenxiao; Qu Ning; Mei Liu; Liu Yu; Wang Xuelian; Yu Xiangru; Liu Zengyan; Nie Dan; Liu Yang; Yan Jinglong; Yang Baofeng; Lu Yanjie^*; Chu Wenfeng

来源：Toxicology Letters, 2013, 219(3): 223-230.

DOI：10.1016/j.toxlet.2013.03.024

• Arsenic trioxide
• Apoptosis
• Cardiac fibroblasts
• TGF-beta

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

• 出版日期2013-6-7
• 单位哈尔滨医科大学