Thrombopoietin protects against doxorubicin-induced cardiomyopathy, improves cardiac function, and reversely alters specific signalling networks

Eur J Heart Fail. 2011 Apr;13(4):366-76. doi: 10.1093/eurjhf/hfr001. Epub 2011 Feb 16.


Aims: 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.

Methods and 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.

Conclusion: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Disease
  • Animals
  • Cardiomyopathies / chemically induced
  • Cardiomyopathies / drug therapy*
  • Cardiomyopathies / physiopathology
  • Chronic Disease
  • Disease Models, Animal
  • Doxorubicin / adverse effects*
  • Gene Expression Profiling
  • Heart / physiopathology*
  • Male
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Thrombopoietin / therapeutic use*
  • Treatment Outcome


  • Doxorubicin
  • Thrombopoietin
  • Proto-Oncogene Proteins c-akt