Author + information
- Xiao-Jing Shi,
- Hui-Min Wang,
- Kai Tang,
- Xin Huang,
- Yue Xiao,
- Renfeng Zhang and
- Wen Zhao
The application of doxorubicin (DOX), a well-known antitumor drug, is limited due to its cumulative cardiotoxicity. Up to now, no effective prevention is available for its side effect. It has been shown that peroxiredoxin II (Prx II) protects cardiomyocytes from oxidative stress-induced injury and the protection of metallothionein against DOX-induced cardiotoxicity is associated with the antioxidant role of prxs. However, it remains to be understood that whether Prx II would exert any protective effects against DOX induced cardiac injury.
In the current study, a transgenic mouse with cardiac-specific prxII overexpression was chosen to determine whether prxII protects DOX-induced cardiac injury.
In the current study, we found that DOX treatment significantly decreased Prx II protein expression, without alteration of other peroxiredoxins, Trx2 and Catalase in wild type mouse hearts. Cardiac-specific overexpression of Prx II significantly ameliorated acute DOX-triggered ROS accumulation and cardiomyocyte apoptosis, as well as exacerbated myocardial dysfunction in an in vivo model of 5 days DOX injection, assessed by echocardiography. The 12-day survival rate was also significantly increased to 1.4 fold in prxII transgenic mice, compared with their wild-type littermates. Furthermore, Prx II transgenic mice showed improved cardiac contractile function and prolonged survival after chronic administration of DOX. The mechanisms underlying these protective effects of Prx II were associated with the prolonged activation of Akt phosphorylations at Ser473 and Thr308 and attenuation of DOX-induced oxidative stress. Accordingly, the protein levels of Bcl-2 were preserved, Bax and cleaved caspase-3 were decreased in Prx II transgenic hearts treated by DOX, compared to the levels of those proteins in WTs.
Our findings indicated that overexpression of Prx II inhibits DOX-triggered cardiac injury and the prolonged Akt activation appears to be involved in the prxII's beneficial effects. Prx II may constitute a new therapeutic approach in ameliorating the cardiotoxic effects of DOX in cancer patients.