title: Senescence marker protein 30 has a cardio-protective role in doxorubicin-induced cardiac dysfunction.
abstract: BACKGROUND
  Senescence marker protein 30 (SMP30), which was originally identified as an aging marker protein, is assumed to act as a novel anti-aging factor in the liver, lungs and brain. We hypothesized that SMP30 has cardio-protective function due to its anti-aging and anti-oxidant effects on doxorubicin (DOX)-induced cardiac dysfunction.
  
  
  RESULTS
  SMP30 knockout (SMP30 KO) mice, SMP30 transgenic (SMP30 TG) mice with cardiac-specific overexpression of SMP30 gene and wild-type (WT) littermate mice at 12-14 weeks of age were given intra-peritoneal injection of DOX (20 mg/kg) or saline. Five days after DOX injection, echocardiography revealed that left ventricular ejection fraction was more severely reduced in the DOX-treated SMP30 KO mice than in the DOX-treated WT mice, but was preserved in the DOX-treated SMP30 TG mice. Generation of reactive oxygen species and oxidative DNA damage in the myocardium were greater in the DOX-treated SMP30 KO mice than in the DOX-treated WT mice, but much less in the SMP30 TG mice. The numbers of deoxynucleotidyltransferase-mediated dUTP nick end-labeling positive nuclei in the myocardium, apoptotic signaling pathways such as caspase-3 activity, Bax/Bcl-2 ratio and phosphorylation activity of c-Jun N-terminal kinase were increased in SMP30 KO mice and decreased in SMP30 TG mice compared with WT mice after DOX injection.
  
  
  CONCLUSIONS
  SMP30 has a cardio-protective role by anti-oxidative and anti-apoptotic effects in DOX-induced cardiotoxicity, and can be a new therapeutic target to prevent DOX-induced heart failure.
authors.affiliation: Department of Cardiology and Hematology, Fukushima Medical University, Fukushima, Japan.
authors.forename: Makiko
authors.initials: M
authors.lastname: Miyata
authors.affiliation: Department of Cardiology and Hematology, Fukushima Medical University, Fukushima, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Suzuki
authors.affiliation: Department of Cardiology and Hematology, Fukushima Medical University, Fukushima, Japan.
authors.forename: Tomofumi
authors.initials: T
authors.lastname: Misaka
authors.affiliation: First Department of Internal Medicine, Yamagata University School of Medicine, Yamagata, Japan.
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Shishido
authors.affiliation: Department of Cardiology and Hematology, Fukushima Medical University, Fukushima, Japan.
authors.forename: Shu-Ichi
authors.initials: S
authors.lastname: Saitoh
authors.affiliation: Molecular Regulation of Aging, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan.
authors.forename: Akihito
authors.initials: A
authors.lastname: Ishigami
authors.affiliation: First Department of Internal Medicine, Yamagata University School of Medicine, Yamagata, Japan.
authors.forename: Isao
authors.initials: I
authors.lastname: Kubota
authors.affiliation: Department of Cardiology and Hematology, Fukushima Medical University, Fukushima, Japan.
authors.forename: Yasuchika
authors.initials: Y
authors.lastname: Takeishi
mesh_terms: D000375:Aging / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001205:Ascorbic Acid / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D002316:Cardiotonic Agents / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D004249:DNA Damage; D004317:Doxorubicin / Q000633:toxicity*; D005355:Fibrosis; D006333:Heart Failure / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology*; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress; D010766:Phosphorylation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D013318:Stroke Volume / Q000187:drug effects / Q000502:physiology; D015854:Up-Regulation; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: C494827:Bax protein, mouse; D015415:Biomarkers; D002135:Calcium-Binding Proteins; D002316:Cardiotonic Agents; D047908:Intracellular Signaling Peptides and Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; C513324:Rgn protein, mouse; D051028:bcl-2-Associated X Protein; C052617:Bcl2 protein, mouse; D004317:Doxorubicin; C505409:Casp3 protein, mouse; D053148:Caspase 3; D001205:Ascorbic Acid