title: Metallothionein prevention of arsenic trioxide-induced cardiac cell death is associated with its inhibition of mitogen-activated protein kinases activation in vitro and in vivo.
abstract: Cardiotoxicity induced by arsenic trioxide has become a serious blockade of clinical applications of this effective anticancer agent. The general mechanism responsible for arsenic cardiotoxicity has been attributed to its induction of oxidative stress. Metallothionein (MT) has been extensively proven to be a potent endogenous antioxidant that protects heart against oxidative stress-induced cardiac damage. To investigate whether and how MT protects against arsenic cardiotoxicity, MT-overexpressing H9c2 (MT-H9c2) cardiac cells and transgenic (MT-TG) mice with their corresponding controls were exposed to the clinical relevant dose of arsenic trioxide. Cardiac cell apoptosis was detected by molecular indices, including the cleavage of caspase 3 and caspase 12, Bax/Bcl2 expression ratio, CHOP expression and/or confirmed by a terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay. Arsenic trioxide dose- and time-dependently induced cardiac cell death in H9c2 cells with a significant activation of major MAPK subfamily members such as ERK1/2, JNK and p38, but not in MT-H9c2 cells. Importantly, the protective effect of MT on arsenic trioxide-induced apoptotic cell death was completely recaptured in the heart of MT-TG with a significant prevention of MAPKs activation. These results indicate that arsenic trioxide-upregulated MAPKs might play important role in arsenic trioxide-induced apoptotic cell death in cardiac cells both in vivo and in vitro, and MT's suppression of arsenic trioxide apoptotic effect was associated with the inhibition of MAPK activation. Therefore, selective elevation of cardiac MT levels with pharmacological approaches may be a potential strategy for the prevention of arsenic cardiotoxicity.
authors.affiliation: The Second Hospital of Jilin University, Changchun 130021, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Miao
authors.forename: Zefang
authors.initials: Z
authors.lastname: Tang
authors.forename: Yonggang
authors.initials: Y
authors.lastname: Wang
authors.forename: Guanfang
authors.initials: G
authors.lastname: Su
authors.forename: Weixia
authors.initials: W
authors.lastname: Sun
authors.forename: Wei
authors.initials: W
authors.lastname: Wei
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.forename: Lining
authors.initials: L
authors.lastname: Miao
authors.forename: Lu
authors.initials: L
authors.lastname: Cai
authors.forename: Yi
authors.initials: Y
authors.lastname: Tan
authors.forename: Qiuju
authors.initials: Q
authors.lastname: Liu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000037:antagonists & inhibitors*; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D020287:In Situ Nick-End Labeling; D008297:Male; D008668:Metallothionein / Q000096:biosynthesis / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects*; D018384:Oxidative Stress / Q000187:drug effects; D010087:Oxides / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D011897:Random Allocation; D051381:Rats; D051742:Transcription Factor CHOP / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D001152:Arsenicals; C497250:Ddit3 protein, mouse; D010087:Oxides; D051028:bcl-2-Associated X Protein; D051742:Transcription Factor CHOP; D008668:Metallothionein; D020928:Mitogen-Activated Protein Kinases; D053148:Caspase 3; D000077237:Arsenic Trioxide