title: Effects of angiotensin-converting enzyme inhibitor on delayed-onset doxorubicin-induced cardiotoxicity.
abstract: Childhood survivors of cancer who are treated with anthacycline chemotherapy, such as doxorubicin (DOX), can develop late-onset cardiomyopathy years after chemotherapy. The mechanism(s) for progression of anthracycline cardiotoxicity to late cardiomyopathy is unknown. Because angiotensin II has been implicated in the progression of other cardiomyopathies, this investigation was undertaken to determine whether treatment with an angiotensinconverting enzyme (ACE) inhibitor, lisinopril, reduces the time-dependent effects of doxorubicin on cardiac gene expression and myocellular apoptosis. A single dose of saline (control) or doxorubicin (DOX treated; 2 mg/kg iv) was administered to rabbits. Control and DOX-treated groups were also subgrouped to receive lisinopril and designated as lisinopril or DOX + lisinopril, respectively (1 mg/kg/d oral), for 10 wk. Histopathology, as determined at the light and ultrastructural level, was consistent with a reduced number of cardiomyocytes relative to interstitial cells in the left ventricle (LV) of the DOX-treated group compared with control and DOX + lisinopril groups. Gene expression of the pro-atrial naturetic peptide (ANP), quantified by steady-state messenger ribonucleic acid (mRNA) levels with reverse transcriptase polymerase chain reaction (RT-PCR) and Southern blotting, increased approx 12-fold (n = 10; p < 0.05) in the LV of DOX-treated groups compared to control and DOX + lisinopril groups. Increased ANP mRNA expression following doxorubicin dosing was localized predominantly in ventricular myocytes by in situ hybridization. Deoxyribonucleic acid (DNA) fragmentation, determined by TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling), was increased in both DOX-treated and DOX + lisinopril groups compared to the control group. Lisinopril prevented both late-onset increased ventricular ANP expression and subsequent DOX-induced myocyte loss. The authors speculate that these protective effects of lisinopril are related to reduced ANP expression and myocyte loss, the latter possibly mediated by effects on myocellular apoptosis.
authors.affiliation: Division of Pediatric Cardiology, Department of Pediatrics, University of South Florida College of Medicine, Tampa/St. Petersburg, FL 33701, USA. boucekr@allkids.org
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Boucek
authors.forename: Ann
authors.initials: A
authors.lastname: Steele
authors.forename: Ann
authors.initials: A
authors.lastname: Miracle
authors.forename: James
authors.initials: J
authors.lastname: Atkinson
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects*; D017209:Apoptosis / Q000187:drug effects; D015139:Blotting, Southern; D004317:Doxorubicin / Q000009:adverse effects*; D005260:Female; D015870:Gene Expression; D006331:Heart Diseases / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D006352:Heart Ventricles / Q000473:pathology; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007262:Infusions, Intravenous; D017706:Lisinopril / Q000494:pharmacology*; D011817:Rabbits; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D000903:Antibiotics, Antineoplastic; D004317:Doxorubicin; D017706:Lisinopril