Protection against Doxorubicin-Induced Cardiac Dysfunction Is Not Maintained Following Prolonged Autophagy Inhibition.
Protection against Doxorubicin-Induced Cardiac Dysfunction Is Not Maintained Following Prolonged Autophagy Inhibition.
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DOI：
10.3390/ijms21218105
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发表时间：
2020-10-30
影响因子：
5.6
通讯作者：
Smuder AJ
中科院分区：
文献类型：
--
作者：
Montalvo RN;Doerr V;Kwon OS;Talbert EE;Yoo JK;Hwang MH;Nguyen BL;Christou DD;Kavazis AN;Smuder AJ
阿霉素(DOX)是一种用于治疗多种癌症的高效化疗药物。然而，众所周知，DOX会促进严重心血管并发症的发生。因此，研究DOX心脏毒性的潜在机制对于制定治疗对策是必要的。在这方面，自噬是一个复杂的分解代谢过程，在DOX暴露后心脏会增加。然而，关于自噬失调在DOX引起的心功能障碍的病因中的作用，存在相互矛盾的证据。本研究旨在通过使用显性负自噬基因5(ATG5)腺相关病毒(rAAV-dnATG5)特异性地抑制自噬小体的形成来阐明自噬在DOX诱导的心脏毒性中的作用。DOX的急性(2天)和延迟(9天)效应(20 mg/kg腹腔注射)对雌性SD大鼠心脏的影响进行了评估。我们的数据证实了DOX对左心功能、氧化还原平衡和线粒体功能的不利影响。有趣的是，在DOX治疗的大鼠中，通过rAAV-dnATG5靶向抑制心脏的自噬可以改善线粒体活性氧释放的增加以及心脏和线粒体功能的减弱，但仅在急性时间点。自噬抑制效应在2天和9天时间点的偏差似乎与ATG5-ATG12结合的不同有关，因为这一自噬形成的标记物在DOX暴露后2天显著升高，但在第9天恢复到基线水平。DOX暴露可能瞬时上调大鼠心脏中的自噬信号；因此，长期抑制自噬可能会导致病理后果。
Doxorubicin (DOX) is a highly effective chemotherapeutic agent used in the treatment of various cancer types. Nevertheless, it is well known that DOX promotes the development of severe cardiovascular complications. Therefore, investigation into the underlying mechanisms that drive DOX-induced cardiotoxicity is necessary to develop therapeutic countermeasures. In this regard, autophagy is a complex catabolic process that is increased in the heart following DOX exposure. However, conflicting evidence exists regarding the role of autophagy dysregulation in the etiology of DOX-induced cardiac dysfunction. This study aimed to clarify the contribution of autophagy to DOX-induced cardiotoxicity by specifically inhibiting autophagosome formation using a dominant negative autophagy gene 5 (ATG5) adeno-associated virus construct (rAAV-dnATG5). Acute (2-day) and delayed (9-day) effects of DOX (20 mg/kg intraperitoneal injection (i.p.)) on the hearts of female Sprague–Dawley rats were assessed. Our data confirm established detrimental effects of DOX on left ventricular function, redox balance and mitochondrial function. Interestingly, targeted inhibition of autophagy in the heart via rAAV-dnATG5 in DOX-treated rats ameliorated the increase in mitochondrial reactive oxygen species emission and the attenuation of cardiac and mitochondrial function, but only at the acute timepoint. Deviation in the effects of autophagy inhibition at the 2- and 9-day timepoints appeared related to differences in ATG5–ATG12 conjugation, as this marker of autophagosome formation was significantly elevated 2 days following DOX exposure but returned to baseline at day 9. DOX exposure may transiently upregulate autophagy signaling in the rat heart; thus, long-term inhibition of autophagy may result in pathological consequences.
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影响因子：
3.4
作者：
McGowan JV;Chung R;Maulik A;Piotrowska I;Walker JM;Yellon DM
通讯作者：
Yellon DM
影响因子：
105.7
作者：
BONADONNA, G;MONFARDINI, S;FOSSATIB.F
通讯作者：
FOSSATIB.F
影响因子：
15.9
作者：
Anderson, Ethan J.;Lustig, Mary E.;Neufer, P. Darrell
通讯作者：
Neufer, P. Darrell
影响因子：
4.8
作者：
Kobayashi, Satoru;Volden, Paul;Liang, Qiangrong
通讯作者：
Liang, Qiangrong
影响因子：
4
作者：
Kim, Young Ae;Cho, Hyunsoon;Kim, Hak Jin
通讯作者：
Kim, Hak Jin