title: Thrombopoietin protects against doxorubicin-induced cardiomyopathy, improves cardiac function, and reversely alters specific signalling networks.
abstract: OBJECTIVE
  We investigated the therapeutic efficacy of thrombopoietin (TPO) in acute and chronic rat models of heart damage and explored the mechanisms in terms of genome-wide transcriptional changes, phosphorylation signals, and bone marrow endothelial progenitor cell (EPC) levels.
  
  
  RESULTS
  Cardiac damage was induced in rat models of (i) acute-doxorubicin (DOX) treatment: single high-dose DOX, four doses TPO, followed up for 5 days; and (ii) chronic-DOX treatment: one low-dose DOX and three doses TPO weekly for 6 weeks, followed up for 11 weeks. Our results demonstrated that TPO treatment led to significant improvements of fractional shortening, cardiac output, and morphologic parameters in both models. In the acute-DOX model, microarray and network analyses showed that DOX damage was associated with changes in a large cohort of gene expressions, of which many were inversely regulated by TPO, including modulators of signal transduction, ion transport, anti-apoptosis, protein kinase B/ p42/p44 extracellular signal-regulated kinase (AKT/ERK) pathways, cell division, and contractile protein/matrix remodelling. Many of these regulations also occurred in chronic-DOX animals, in which TPO treatment reduced morphological damage and cardiomyopathy score, and increased AKT phosphorylation of heart tissues. Thrombopoietin also increased EPC colonies in their bone marrow.
  
  
  CONCLUSIONS
  Our overall data suggest that TPO promotes cardiac protection from acute- and chronic-DOX insults, possibly mediated by multi-factorial mechanisms including AKT- and ERK-associated restoration of regulatory gene activities critical for normal heart function.
authors.affiliation: Department of Paediatrics, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Kathy Yuen-Yee
authors.initials: KY
authors.lastname: Chan
authors.forename: Ping
authors.initials: P
authors.lastname: Xiang
authors.forename: Ligang
authors.initials: L
authors.lastname: Zhou
authors.forename: Karen
authors.initials: K
authors.lastname: Li
authors.forename: Pak-Cheung
authors.initials: PC
authors.lastname: Ng
authors.forename: Chi-Chiu
authors.initials: CC
authors.lastname: Wang
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.forename: Hai-Yan
authors.initials: HY
authors.lastname: Deng
authors.forename: Nga-Hin
authors.initials: NH
authors.lastname: Pong
authors.forename: Hailu
authors.initials: H
authors.lastname: Zhao
authors.forename: Wood-Yee
authors.initials: WY
authors.lastname: Chan
authors.forename: Rita Yn-Tz
authors.initials: RY
authors.lastname: Sung
mesh_terms: D000208:Acute Disease; D000818:Animals; D009202:Cardiomyopathies / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D002908:Chronic Disease; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000009:adverse effects*; D020869:Gene Expression Profiling; D006321:Heart / Q000503:physiopathology*; D008297:Male; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013926:Thrombopoietin / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D004317:Doxorubicin; D013926:Thrombopoietin; D051057:Proto-Oncogene Proteins c-akt