Global gene expression profiles of MT knockout and wild-type mice in the condition of doxorubicin-induced cardiomyopathy.
Increasing evidence from in vivo and in vitro studies has indicated that MT exerts protective effects against DOX-induced cardiotoxicity; however the underlying precise mechanisms still remain an enigma. Therefore, the present study was designed using MT knockout mice in concert with genomic approaches to explore the possible molecular and cellular mechanisms in terms of the genetic network changes. MT-I/II null (MT⁻/⁻) mice and corresponding wild-type mice (MT+/+) were administrated with a single dose of DOX (15 mg/kg, i.p.) or equal volume of saline. Animals were sacrificed on the 4th day after DOX administration and samples were collected for further analyses. Global gene expression profiles of cardiac mRNA from two genotype mice revealed that 381 characteristically MT-responsive genes were identified between MT+/+ mice and MT⁻/⁻ mice in response to DOX, including fos, ucp3, car3, atf3, map3k6, etc. Functional analysis implied MAPK signaling pathway, p53 signaling pathway, Jak-STAT signaling pathway, PPAR signaling pathway, Wnt signaling pathway, etc. might be involved to mediate the protection of DOX cardiomyopathy by MT. Results from the present study not only validated the previously reported possible mechanisms of MT protection against DOX toxicity, but also provided new clues into the molecular mechanisms involved in this process.
Evaluation and Research Center for Toxicology, Institute of Disease Control and Prevention, Academy of Military Medical Science, 20 Dongdajie Street, Fengtai District, Beijing 100071, PR China.
Yi
Y
Shuai
Jun
J
Guo
Yansheng
Y
Dong
Weijian
W
Zhong
Ping
P
Xiao
Tong
T
Zhou
Lishi
L
Zhang
Shuangqing
S
Peng
D000818:Animals; D009202:Cardiomyopathies / Q000139:chemically induced* / Q000235:genetics; D003402:Creatine Kinase / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology*; D020869:Gene Expression Profiling; D005796:Genes / Q000235:genetics; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D008668:Metallothionein / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D014158:Transcription, Genetic / Q000235:genetics
D004317:Doxorubicin; D008668:Metallothionein; D007770:L-Lactate Dehydrogenase; D003402:Creatine Kinase