title: Erythropoietin preserves the endothelial differentiation capacity of cardiac progenitor cells and reduces heart failure during anticancer therapies.
abstract: Anticancer therapies, such as targeting of STAT3 or the use of anthracyclins (doxorubicin), can induce cardiomyopathy. In mice prone to developing heart failure as a result of reduced cardiac STAT3 expression (cardiomyocyte-restricted deficiency of STAT3) or treatment with doxorubicin, we observed impaired endothelial differentiation capacity of Sca-1(+) cardiac progenitor cells (CPCs) in conjunction with attenuated CCL2/CCR2 activation. Mice in both models also displayed reduced erythropoietin (EPO) levels in the cardiac microenvironment. EPO binds to CPCs and seems to be responsible for maintaining an active CCL2/CCR2 system. Supplementation with the EPO derivative CERA in a hematocrit-inactive low dose was sufficient to upregulate CCL2, restore endothelial differentiation of CPCs, and preserve the cardiac microvasculature and cardiac function in both mouse models. Thus, low-dose EPO treatment could potentially be exploited as a therapeutic strategy to reduce the risk of heart failure in certain treatment regimens.
authors.affiliation: Department of Cardiology and Angiology, Medical School Hannover, 30625 Hannover, Germany.
authors.forename: Melanie
authors.initials: M
authors.lastname: Hoch
authors.forename: Philipp
authors.initials: P
authors.lastname: Fischer
authors.forename: Britta
authors.initials: B
authors.lastname: Stapel
authors.forename: Ewa
authors.initials: E
authors.lastname: Missol-Kolka
authors.forename: Belaid
authors.initials: B
authors.lastname: Sekkali
authors.forename: Michaela
authors.initials: M
authors.lastname: Scherr
authors.forename: Fabrice
authors.initials: F
authors.lastname: Favret
authors.forename: Thomas
authors.initials: T
authors.lastname: Braun
authors.forename: Matthias
authors.initials: M
authors.lastname: Eder
authors.forename: Karin
authors.initials: K
authors.lastname: Schuster-Gossler
authors.forename: Achim
authors.initials: A
authors.lastname: Gossler
authors.forename: Andres
authors.initials: A
authors.lastname: Hilfiker
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Balligand
authors.forename: Helmut
authors.initials: H
authors.lastname: Drexler
authors.forename: Denise
authors.initials: D
authors.lastname: Hilfiker-Kleiner
mesh_terms: D017667:Adipocytes / Q000166:cytology / Q000187:drug effects; D000818:Animals; D000950:Antigens, Ly / Q000378:metabolism; D000970:Antineoplastic Agents / Q000009:adverse effects*; D002196:Capillaries / Q000187:drug effects / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects*; D004317:Doxorubicin / Q000494:pharmacology / Q000627:therapeutic use; D042783:Endothelial Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D004921:Erythropoietin / Q000494:pharmacology* / Q000627:therapeutic use; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D017353:Gene Deletion; D006333:Heart Failure / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D006334:Heart Function Tests / Q000187:drug effects; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000473:pathology*; D009928:Organ Specificity / Q000187:drug effects; D020286:Pericytes / Q000166:cytology / Q000187:drug effects; D054390:Receptors, CCR2 / Q000378:metabolism; D017467:Receptors, Erythropoietin / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D016019:Survival Analysis; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: D000950:Antigens, Ly; D000970:Antineoplastic Agents; C515335:Ccr2 protein, mouse; C074650:Ly6a protein, mouse; D008565:Membrane Proteins; D054390:Receptors, CCR2; D017467:Receptors, Erythropoietin; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D004921:Erythropoietin; D004317:Doxorubicin; D040301:Vascular Endothelial Growth Factor Receptor-2