title: Anthracycline cardiomyopathy is mediated by depletion of the cardiac stem cell pool and is rescued by restoration of progenitor cell function.
abstract: BACKGROUND
  Anthracyclines are the most effective drugs available in the treatment of neoplastic diseases; however, they have profound consequences on the structure and function of the heart, which over time cause a cardiomyopathy that leads to congestive heart failure.
  
  
  RESULTS
  Administration of doxorubicin in rats led to a dilated myopathy, heart failure, and death. To test whether the effects of doxorubicin on cardiac anatomy and function were mediated by alterations in cardiac progenitor cells (CPCs), these cells were exposed to the anthracycline, which increased the formation of reactive oxygen species and caused increases in DNA damage, expression of p53, telomere attrition, and apoptosis. Additionally, doxorubicin resulted in cell-cycle arrest at the G2/M transition, which led to a significant decrease in CPC growth. Doxorubicin elicited multiple molecular adaptations; the massive apoptotic death that occurred in CPCs in the presence of anthracycline imposed on the surviving CPC pool the activation of several pathways aimed at preservation of the primitive state, cell division, lineage differentiation, and repair of damaged DNA. To establish whether delivery of syngeneic progenitor cells opposed the progression of doxorubicin cardiotoxicity, enhanced green fluorescent protein-labeled CPCs were injected in the failing myocardium; this treatment promoted regeneration of cardiomyocytes and vascular structures, which improved ventricular performance and rate of animal survival.
  
  
  CONCLUSIONS
  Our results raise the possibility that autologous CPCs can be obtained before antineoplastic drugs are given to cancer patients and subsequently administered to individuals who are particularly sensitive to the cardiotoxicity of these agents for prevention or management of heart failure.
authors.affiliation: Department of Experimental Medicine, Section of Pharmacology, Second Naples Medical School, Naples, Italy. panversa@partners.org
authors.forename: Antonella
authors.initials: A
authors.lastname: De Angelis
authors.forename: Elena
authors.initials: E
authors.lastname: Piegari
authors.forename: Donato
authors.initials: D
authors.lastname: Cappetta
authors.forename: Laura
authors.initials: L
authors.lastname: Marino
authors.forename: Amelia
authors.initials: A
authors.lastname: Filippelli
authors.forename: Liberato
authors.initials: L
authors.lastname: Berrino
authors.forename: João
authors.initials: J
authors.lastname: Ferreira-Martins
authors.forename: Hanqiao
authors.initials: H
authors.lastname: Zheng
authors.forename: Toru
authors.initials: T
authors.lastname: Hosoda
authors.forename: Marcello
authors.initials: M
authors.lastname: Rota
authors.forename: Konrad
authors.initials: K
authors.lastname: Urbanek
authors.forename: Jan
authors.initials: J
authors.lastname: Kajstura
authors.forename: Annarosa
authors.initials: A
authors.lastname: Leri
authors.forename: Francesco
authors.initials: F
authors.lastname: Rossi
authors.forename: Piero
authors.initials: P
authors.lastname: Anversa
mesh_terms: D000818:Animals; D018943:Anthracyclines / Q000009:adverse effects*; D009202:Cardiomyopathies / Q000139:chemically induced* / Q000473:pathology / Q000628:therapy*; D002311:Cardiomyopathy, Dilated / Q000139:chemically induced / Q000473:pathology / Q000628:therapy; D002452:Cell Count; D004317:Doxorubicin / Q000009:adverse effects; D006333:Heart Failure / Q000139:chemically induced / Q000473:pathology / Q000628:therapy; D006801:Humans; D032383:Myocytes, Cardiac; D009369:Neoplasms / Q000150:complications / Q000188:drug therapy; D051381:Rats; D012038:Regeneration; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000187:drug effects* / Q000502:physiology
chemical_list: D018943:Anthracyclines; D004317:Doxorubicin