Boucek Robert J, Steele Ann, Miracle Ann, Atkinson James
Division of Pediatric Cardiology, Department of Pediatrics, University of South Florida College of Medicine, Tampa/St. Petersburg, FL 33701, USA.
Cardiovasc Toxicol. 2003;3(4):319-29. doi: 10.1385/ct:3:4:319.
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.
接受蒽环类化疗药物（如阿霉素，DOX）治疗的癌症儿童幸存者，在化疗数年之后可能会出现迟发性心肌病。蒽环类药物心脏毒性进展为晚期心肌病的机制尚不清楚。由于血管紧张素II与其他心肌病的进展有关，因此进行了这项研究，以确定使用血管紧张素转换酶（ACE）抑制剂赖诺普利治疗是否能降低阿霉素对心脏基因表达和心肌细胞凋亡的时间依赖性影响。给兔子单次注射生理盐水（对照组）或阿霉素（DOX治疗组；2mg/kg静脉注射）。对照组和DOX治疗组也再分为接受赖诺普利治疗的亚组，分别命名为赖诺普利组或DOX+赖诺普利组（1mg/kg/d口服），持续10周。在光镜和超微结构水平上确定的组织病理学结果显示，与对照组和DOX+赖诺普利组相比，DOX治疗组左心室（LV）中心肌细胞数量相对于间质细胞数量减少。通过逆转录聚合酶链反应（RT-PCR）和Southern印迹法，以稳态信使核糖核酸（mRNA）水平定量测定的心房利钠肽（ANP）基因表达，在DOX治疗组的LV中比对照组和DOX+赖诺普利组增加了约12倍（n = 10；p < 0.05）。通过原位杂交发现，阿霉素给药后ANP mRNA表达增加主要定位于心室肌细胞。通过TUNEL（末端脱氧核苷酸转移酶介导的dUTP缺口末端标记）测定的脱氧核糖核酸（DNA）片段化，在DOX治疗组和DOX+赖诺普利组中均比对照组增加。赖诺普利可预防晚期心室ANP表达增加以及随后DOX诱导的心肌细胞丢失。作者推测，赖诺普利的这些保护作用与ANP表达降低和心肌细胞丢失减少有关，后者可能是通过对心肌细胞凋亡的影响介导的。
