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Thrombopoietin protects against doxorubicin‐induced cardiomyopathy, improves cardiac function, and reversely alters specific signalling networks
Author(s) -
Chan Kathy YuenYee,
Xiang Ping,
Zhou Ligang,
Li Karen,
Ng PakCheung,
Wang ChiChiu,
Zhang Lei,
Deng HaiYan,
Pong NgaHin,
Zhao Hailu,
Chan WoodYee,
Sung Rita YnTz
Publication year - 2011
Publication title -
european journal of heart failure
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.149
H-Index - 133
eISSN - 1879-0844
pISSN - 1388-9842
DOI - 10.1093/eurjhf/hfr001
Subject(s) - medicine , thrombopoietin , phospholamban , protein kinase b , heart failure , mapk/erk pathway , cardiac function curve , dilated cardiomyopathy , signal transduction , cardioprotection , pharmacology , endocrinology , cancer research , myocardial infarction , microbiology and biotechnology , biology , haematopoiesis , stem cell
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.