Pretreatment with angiotensin-converting enzyme inhibitor improves doxorubicin-induced cardiomyopathy via preservation of mitochondrial function.
Pretreatment with angiotensin-converting enzyme inhibitor improves doxorubicin-induced cardiomyopathy via preservation of mitochondrial function.
复制标题
DOI：
10.1016/j.jtcvs.2010.07.097
复制
发表时间：
2011-08
影响因子：
6
通讯作者：
Wu, Joseph C.
中科院分区：
文献类型：
--
作者：
Hiona, Asimina;Lee, Andrew Stephen;Nagendran, Jayan;Xie, Xiaoyan;Connolly, Andrew J.;Robbins, Robert C.;Wu, Joseph C.
阿霉素是一种广泛使用的化疗药物，但其应用与心脏毒性有关。自由基的产生和线粒体功能障碍被认为是多柔比星诱导的心力衰竭的原因。血管紧张素转换酶（ACE）抑制剂通常用作心脏保护剂，最近在临床研究中显示可有效预防蒽环类药物诱导的心力衰竭。在这里，我们评估了这些保护作用的机制，通过测试的ACE抑制剂依那普利的能力，以保护线粒体功能的慢性阿霉素治疗大鼠模型。将Sprague道利大鼠分成三组，并跟踪总共10周：a）对照-未处理，B）多柔比星处理（Dox），和c）多柔比星+依那普利处理（DE）。从第2周至第7周，以每周间隔通过腹膜内注射给予多柔比星。在研究期间，DE组饮用水中给予依那普利。多柔比星治疗导致左心室收缩力显著丧失（P< 0.05），线粒体功能通过状态3呼吸受损而降低，ATP胞浆分数降低，自由基产生上调。依那普利可显著减轻收缩率的降低（P< 0.05），并阻止多柔比星相关的呼吸效率和胞浆ATP含量的降低（P< 0.05）。重要的是，依那普利还消除了强力阿霉素诱导的自由基形成增加。依那普利通过保护线粒体呼吸效率和减少多柔比星相关自由基的产生减轻多柔比星诱导的心功能障碍。
Doxorubicin is a widely used chemotherapy drug, but its application is associated with cardiotoxicity. Free radical generation and mitochondrial dysfunction are thought to contribute to doxorubicin-induced cardiac failure. Angiotensin-converting enzyme (ACE) inhibitors are commonly used as cardioprotective agents and have recently been shown in clinical studies to be efficacious in the prevention of anthracycline induced heart failure. Here we evaluated a mechanism for these protective effects by testing the ability of the ACE inhibitor enalapril to preserve mitochondrial function in a model of chronic doxorubicin treatment in rats. Sprague Dawley rats were divided into three groups and followed for a total of 10 weeks: a) control-untreated, b) Doxorubicin treated (Dox), and c) Doxorubicin + Enalapril treated (DE). Doxorubicin was administered via intraperitoneal injection at weekly intervals from week 2 through week 7. Enalapril was administered in the drinking water of the DE group for the study duration. Doxorubicin treatment produced a significant loss in left ventricular contractility (P< 0.05), decrease in mitochondrial function via impairment of state-3 respiration, decrease in the cytosolic fraction of ATP, and up-regulation of free radical production. Enalapril significantly attenuated the decrease in percent fractional shortening (P< 0.05) and prevented the doxorubicin-associated reduction in respiratory efficiency and cytosolic ATP content (P< 0.05). Importantly, enalapril also abolished the robust doxorubicin-induced increase in free radical formation. Administration of enalapril attenuates doxorubicin-induced cardiac dysfunction via preservation of mitochondrial respiratory efficiency and reduction in doxorubicin-associated free radical generation.
登录
查看更多内容
影响因子：
158.5
作者：
PFEFFER, MA;BRAUNWALD, E;HAWKINS, CM
通讯作者：
HAWKINS, CM
影响因子：
37.8
作者：
ADER, R;CHATTERJEE, K;PARMLEY, W
通讯作者：
PARMLEY, W
DOI：
10.1016/s0022-2828(95)91551-6
发表时间：
1995-10-01
影响因子：
5
作者：
SANBE, A;TANONAKA, K;TAKEO, S
通讯作者：
TAKEO, S
影响因子：
37.8
作者：
Zhu, Wuqiang;Soonpaa, Mark H.;Chen, Hanying;Shen, Weihua;Payne, R. Mark;Liechty, Edward A.;Caldwell, Randall L.;Shou, Weinian;Field, Loren J.
通讯作者：
Field, Loren J.
影响因子：
3.9
作者：
Konorev, EA;Kennedy, MC;Kalyanaraman, B
通讯作者：
Kalyanaraman, B