Differential roles of nitric oxide synthase isozymes in cardiotoxicity and mortality following chronic doxorubicin treatment in mice.
Differential roles of nitric oxide synthase isozymes in cardiotoxicity and mortality following chronic doxorubicin treatment in mice.
复制标题
一氧化氮合酶同工酶在小鼠慢性阿霉素治疗后的心脏毒性和死亡率中的差异作用。
DOI：
10.1007/s00210-009-0407-y
复制
发表时间：
2009-07
影响因子：
3.6
通讯作者：
Wojnowski, Leszek
中科院分区：
文献类型：
--
作者：
Deng, Shiwei;Kruger, Anke;Schmidt, Albrecht;Metzger, Annegret;Yan, Tiandong;Goedtel-Armbrust, Ute;Hasenfuss, Gerd;Brunner, Friedrich;Wojnowski, Leszek
单个一氧化氮合酶（NOS）在蒽环类药物相关心脏毒性中的作用尚不完全清楚。我们研究了阿霉素 (DOX) 长期治疗对单个 NOS 同工酶敲除以及对心肌 eNOS 过度表达的转基因小鼠的影响。在未经处理的纯合 nNOS 和 iNOS 敲除以及 eNOS 转基因中，缩短分数 (FS) 有所减少。 DOX 诱导的野生型小鼠 FS 降低仅在 eNOS 敲除中减弱，而 eNOS 敲除过度表达 nNOS。在 DOX 处理的 eNOS 转基因和 iNOS 敲除中没有观察到收缩性恶化。尽管经 DOX 治疗的幸存 nNOS 敲除模型没有表现出收缩力进一步受损，但大多数 (70%) 动物在治疗开始后 7 周内死亡。与未经处理的野生型心脏相比，DOX 处理的野生型小鼠以及所有三种未经处理的基因敲除小鼠的心脏中一氧化氮 (NO) 水平较低。 DOX 处理对敲除中的 NO 没有影响。这些数据表明单个 NOS 在 DOX 诱导的心脏毒性中的不同作用。 eNOS 缺失所赋予的针对 DOX 效应的保护作用可能是通过 nNOS 的补偿性过度表达介导的。基于 NOS 抑制的预防蒽环类药物引起的心脏毒性应该是 eNOS 选择性的，同时避免抑制 nNOS。
The roles of individual nitric oxide synthases (NOS) in anthracycline-related cardiotoxicity are not completely understood. We investigated the effects of a chronic treatment with doxorubicin (DOX) on knockouts of the individual NOS isozymes and on transgenic mice with myocardial overexpression of eNOS. Fractional shortening (FS) was reduced in untreated homozygous nNOS and iNOS knockouts as well as in eNOS transgenics. DOX-induced FS decrease in wild-type mice was attenuated only in eNOS knockouts, which were found to overexpress nNOS. No worsening of contractility was observed in DOX-treated eNOS transgenics and iNOS knockouts. Although the surviving DOX-treated nNOS knockouts exhibited no further impairment in contractility, most (70%) animals died within 7 weeks after treatment onset. In comparison to untreated wild-type hearts, the nitric oxide (NO) level was lower in hearts from DOX-treated wild-type mice and in all three untreated knockouts. DOX treatment had no effect on NO in the knockouts. These data indicate differential roles of the individual NOS in DOX-induced cardiotoxicity. Protection against DOX effects conferred by eNOS deletion may be mediated by a compensatory overexpression of nNOS. NOS inhibition-based prevention of anthracycline-induced cardiotoxicity should be eNOS-selective, simultaneously avoiding inhibiting nNOS.
登录
查看更多内容
影响因子：
4.6
作者：
Mungrue, Imran N;Husain, Mansoor;Stewart, Duncan J
通讯作者：
Stewart, Duncan J
影响因子：
3.9
作者：
Kassner, Nina;Huse, Klaus;Wojnowski, Leszek
通讯作者：
Wojnowski, Leszek
影响因子：
8.4
作者：
van Dalen, Elvira C.;van der Pal, Helena J. H.;Kremer, Leontien C. M.
通讯作者：
Kremer, Leontien C. M.
影响因子：
11.2
作者：
Lyu, Yi Lisa;Kerrigan, John E.;Liu, Leroy F.
通讯作者：
Liu, Leroy F.
影响因子：
5.7
作者：
Chaiswing, L;Cole, MP;Oberley, TD
通讯作者：
Oberley, TD