Effects of angiotensin-converting enzyme inhibitor on delayed-onset doxorubicin-induced cardiotoxicity.
Effects of angiotensin-converting enzyme inhibitor on delayed-onset doxorubicin-induced cardiotoxicity.
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DOI：
10.1385/ct:3:4:319
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发表时间：
2003-01-01
影响因子：
3.2
通讯作者：
Atkinson, James
中科院分区：
文献类型：
--
作者：
Boucek, Robert J Jr;Steele, Ann;Atkinson, James
接受蒽环类药物化疗（如多柔比星（DOX））的癌症儿童幸存者可能在化疗后数年发生迟发性心肌病。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，本研究旨在确定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作用。将单剂量的盐水（对照）或多柔比星（DOX处理的; 2 mg/kg iv）施用给兔。对照组和DOX治疗组也被分组接受赖诺普利，并分别指定为赖诺普利或DOX +赖诺普利（1 mg/kg/d口服），持续10周。在光和超微结构水平测定的组织学与DOX治疗组与对照组和DOX +赖诺普利组相比，左心室（LV）中心肌细胞相对于间质细胞数量减少一致。用逆转录酶聚合酶链反应（RT-PCR）和Southern印迹通过稳态信使核糖核酸（mRNA）水平定量的前心房利钠肽（ANP）的基因表达，与对照组和DOX +赖诺普利组相比，DOX治疗组的LV中增加约12倍（n = 10; p < 0.05）。通过原位杂交，阿霉素给药后ANP mRNA表达增加主要位于心室肌细胞。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）断裂在DOX治疗组和DOX +赖诺普利组中均比对照组增加。赖诺普利可预防迟发性心室ANP表达增加和随后的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降低ANP表达和心肌细胞损失有关，后者可能通过对心肌细胞凋亡的影响介导。
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.