Anthracycline Cardiomyopathy Is Mediated by Depletion of the Cardiac Stem Cell Pool and Is Rescued by Restoration of Progenitor Cell Function

• Published in: Circulation (New York, N.Y.) Vol. 121; no. 2; pp. 276 - 292
• Main Authors: DE ANGELIS, Antonella, PIEGARI, Elena, URBANEK, Konrad, KAJSTURA, Jan, LERI, Annarosa, ROSSI, Francesco, ANVERSA, Piero, CAPPETTA, Donato, MARINO, Laura, FILIPPELLI, Amelia, BERRINO, Liberato, FERREIRA-MARTINS, Joao, HANQIAO ZHENG, HOSODA, Toru, ROTA, Marcello
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 19-01-2010
• Subjects: Animals; Anthracyclines - adverse effects; Biological and medical sciences; Blood and lymphatic vessels; Blood vessels and receptors; Cardiology. Vascular system; Cardiomyopathies - chemically induced; Cardiomyopathies - pathology; Cardiomyopathies - therapy; Cardiomyopathy, Dilated - chemically induced; Cardiomyopathy, Dilated - pathology; Cardiomyopathy, Dilated - therapy; Cell Count; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Doxorubicin - adverse effects; Fundamental and applied biological sciences. Psychology; Heart Failure - chemically induced; Heart Failure - pathology; Heart Failure - therapy; Humans; Medical sciences; Myocytes, Cardiac; Neoplasms - complications; Neoplasms - drug therapy; Rats; Regeneration; Stem Cell Transplantation; Stem Cells - drug effects; Stem Cells - physiology; Vertebrates: cardiovascular system; Antineoplastic agent; Heart failure; stem cells; antineoplastic agents; cardiotoxicity; Depletion; Cardiomyopathy; Heart disease; Stem cell; Cardiovascular disease; Myocardial disease; Progenitor cell
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/circulationaha.109.895771

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.
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.
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.