Juvenile Exposure to Anthracyclines Impairs Cardiac Progenitor Cell Function and Vascularization Resulting in Greater Susceptibility to Stress-Induced Myocardial Injury in Adult Mice

• Published in: Circulation (New York, N.Y.) Vol. 121; no. 5; pp. 675 - 683
• Main Authors: CHENGQUN HUANG, XIAOXUE ZHANG, GUSTAFSSON, Asa B, RAMIL, Jennifer M, RIKKA, Shivaji, KIM, Lucy, LEE, Youngil, GUDE, Natalie A, THISTLETHWAITE, Patricia A, SUSSMAN, Mark A, GOTTLIEB, Roberta A
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 09-02-2010
• Subjects: Aging - drug effects; Aging - metabolism; Aging - pathology; Animals; Antibiotics, Antineoplastic - adverse effects; Antibiotics, Antineoplastic - pharmacology; Biological and medical sciences; Blood and lymphatic vessels; Blood vessels and receptors; Cardiology. Vascular system; Cardiotoxins - adverse effects; Cardiotoxins - pharmacology; Child; Child, Preschool; Coronary Circulation - drug effects; Coronary Vessel Anomalies - chemically induced; Coronary Vessel Anomalies - metabolism; Coronary Vessel Anomalies - pathology; Disease Susceptibility - chemically induced; Disease Susceptibility - metabolism; Disease Susceptibility - pathology; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Doxorubicin - adverse effects; Doxorubicin - pharmacology; Fundamental and applied biological sciences. Psychology; Humans; Medical sciences; Mice; Myocardial Infarction - chemically induced; Myocardial Infarction - metabolism; Myocardial Infarction - pathology; Myocardium - metabolism; Myocardium - pathology; Neoplasms - drug therapy; Stem Cells - metabolism; Stem Cells - pathology; Stress, Physiological - drug effects; Vertebrates: cardiovascular system; Myocardial infarction; Heart failure; vasculature; Rodentia; Cardiovascular disease; progenitor cells; Coronary heart disease; Myocardial disease; Stress; Vascularization; Angiogenesis; Vertebrata; Mammalia; Mouse; Animal; anthracyclines; Progenitor cell
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/circulationaha.109.902221

The anthracycline doxorubicin is an effective chemotherapeutic agent used to treat pediatric cancers but is associated with cardiotoxicity that can manifest many years after the initial exposure. To date, very little is known about the mechanism of this late-onset cardiotoxicity.
To understand this problem, we developed a pediatric model of late-onset doxorubicin-induced cardiotoxicity in which juvenile mice were exposed to doxorubicin, using a cumulative dose that did not induce acute cardiotoxicity. These mice developed normally and had no obvious cardiac abnormalities as adults. However, evaluation of the vasculature revealed that juvenile doxorubicin exposure impaired vascular development, resulting in abnormal vascular architecture in the hearts with less branching and decreased capillary density. Both physiological and pathological stress induced late-onset cardiotoxicity in the adult doxorubicin-treated mice. Moreover, adult mice subjected to myocardial infarction developed rapid heart failure, which correlated with a failure to increase capillary density in the injured area. Progenitor cells participate in regeneration and blood vessel formation after a myocardial infarction, but doxorubicin-treated mice had fewer progenitor cells in the infarct border zone. Interestingly, doxorubicin treatment reduced proliferation and differentiation of the progenitor cells into cells of cardiac lineages.
Our data suggest that anthracycline treatment impairs vascular development as well as progenitor cell function in the young heart, resulting in an adult heart that is more susceptible to stress.