title: Cardioprotection against doxorubicin by metallothionein Is associated with preservation of mitochondrial biogenesis involving PGC-1α pathway.
abstract: Metallothionein (MT) has been shown to inhibit cardiac oxidative stress and protect against the cardiotoxicity induced by doxorubicin (DOX), a potent and widely used chemotherapeutic agent. However, the mechanism of MT׳s protective action against DOX still remains obscure. Mitochondrial biogenesis impairment has been implicated to play an important role in the etiology and progression of DOX-induced cardiotoxicity. Increasing evidence indicates an intimate link between MT-mediated cardioprotection and mitochondrial biogenesis. This study was aimed to explore the possible contribution of mitochondrial biogenesis in MT׳s cardioprotective action against DOX. Adult male MT-I/II-null (MT(-/-)) and wild-type (MT(+/+)) mice were given a single dose of DOX intraperitoneally. Our results revealed that MT deficiency significantly sensitized mice to DOX-induced cardiac dysfunction, ultrastructural alterations, and mortality. DOX disrupted cardiac mitochondrial biogenesis indicated by mitochondrial DNA copy number and decreased mitochondrial number, and these effects were greater in MT(-/-) mice. Basal MT effectively protected against DOX-induced inhibition on the peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), a key regulator of mitochondrial biogenesis, and its downstream factors including mitochondrial transcription factor A. Moreover, MT was found to preserve the protein expression of manganese superoxide dismutase, a transcriptional target of PGC-1α. in vitro study showed that MT absence augmented DOX-induced increase of mitochondrial superoxide production in primary cultured cardiomyocytes. These findings suggest that MT׳s cardioprotection against DOX is mediated, at least in part, by preservation of mitochondrial biogenesis involving PGC-1α pathway.
authors.affiliation: Evaluation and Research Centre for Toxicology, Institute of Disease Control and Prevention, the Academy of Military Medical Sciences, Beijing, PR China.
authors.forename: Jiabin
authors.initials: J
authors.lastname: Guo
authors.affiliation: Evaluation and Research Centre for Toxicology, Institute of Disease Control and Prevention, the Academy of Military Medical Sciences, Beijing, PR China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Guo
authors.affiliation: Evaluation and Research Centre for Toxicology, Institute of Disease Control and Prevention, the Academy of Military Medical Sciences, Beijing, PR China.
authors.forename: Haiqing
authors.initials: H
authors.lastname: Fang
authors.affiliation: Evaluation and Research Centre for Toxicology, Institute of Disease Control and Prevention, the Academy of Military Medical Sciences, Beijing, PR China.
authors.forename: Lei
authors.initials: L
authors.lastname: Lei
authors.affiliation: Evaluation and Research Centre for Toxicology, Institute of Disease Control and Prevention, the Academy of Military Medical Sciences, Beijing, PR China.
authors.forename: Tingfen
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Evaluation and Research Centre for Toxicology, Institute of Disease Control and Prevention, the Academy of Military Medical Sciences, Beijing, PR China.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Evaluation and Research Centre for Toxicology, Institute of Disease Control and Prevention, the Academy of Military Medical Sciences, Beijing, PR China. Electronic address: pengsq@hotmail.com.
authors.forename: Shuangqing
authors.initials: S
authors.lastname: Peng
mesh_terms: D000818:Animals; D004268:DNA-Binding Proteins / Q000378:metabolism; D004317:Doxorubicin / Q000009:adverse effects*; D055786:Gene Knockout Techniques; D006321:Heart / Q000502:physiology; D006609:High Mobility Group Proteins / Q000378:metabolism; D008297:Male; D008668:Metallothionein / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D006609:High Mobility Group Proteins; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; C081930:Tfam protein, mouse; D014157:Transcription Factors; D004317:Doxorubicin; D008668:Metallothionein
keywords: Cardiotoxicity; Doxorubicin; Doxorubicin (PubChem CID: 23214928); Metallothionein; Mitochondrial biogenesis; PGC-1α