Abstract
Doxorubicin (Dox) is a major anticancer chemotherapeutic agent. However, it causes cardiomyopathy due to the side effect of cardiomyocyte apoptosis. We have previously reported that angiopoietin-1 significantly reduced myocardial infarction after ischemic injury and protected cardiomyocytes from oxidative stress-induced apoptosis. It is hypothesized that angiopoietin-1 may protect cardiomyocytes from Dox-induced apoptosis. Cardiomyocytes H9C2 were transfected with adenovirus expressing angiopoietin-1 (Ad5-Ang-1) 24 h before the cells were challenged with Dox at a concentration of 2 μmol/L. Ad5-GFP served as the vector control. Cardiomyocyte apoptosis was evaluated using Annexin V-FITC staining and caspase-3 and caspase-8 activity was determined by Western blotting. The results showed that Dox treatment significantly induced cardiomyocyte apoptosis as evidenced by the greater number of Annexin V-FITC stained cells and increases in caspase-3 and caspase-8 activity. In contrast, overexpression of angiopoietin-1 significantly prevented Dox-induced cardiomyocyte apoptosis. To elucidate the mechanisms by which angiopoietin-1 protected cells from Dox-induced apoptosis, we analyzed both extrinsic and intrinsic apoptotic signaling pathways. We observed that angiopoietin-1 prevented Dox-induced activation of both extrinsic and intrinsic apoptotic signaling pathways. Specifically, angiopoietin-1 prevented DOX-induced in-creases in FasL and Bax levels and cleaved caspase-3 and caspase-8 levels in H9C2 cells. In addition, overexpression of angiopoietin-1 also activated the pro-survival phosphoinositide-3 kinase (PI3K)/Akt signaling pathway and decreased Dox-induced nuclear factor-kappaB (NF-κB) activation. Our data suggest that promoting the expression of angiopoietin-1 could be a potential approach for reducing Dox-induced cardiomyocyte cytoxicity.
Highlights
Doxorubicin (Dox) is one of the most potent and effective chemotherapeutic agents for the treatment of various types of cancers[1]
To investigate the effect of overexpression of Ang1 on DOX-induced apoptosis in cardiomyocytes, we employed flow cytometry to detect apoptotic cells stained with Annexin V-FITC
We aimed to determine the effect of Ang-1 overexpression on Dox-induced apoptosis in H9C2 cardiomyocytes
Summary
Doxorubicin (Dox) is one of the most potent and effective chemotherapeutic agents for the treatment of various types of cancers[1]. The dosedependent chronic cardiac toxicity of Dox limits its clinical application and may lead to cardiomyopathy and heart failure[2]. It has been reported that reactive oxygen species generation and myocardial apoptosis may be responsible for the pathogenesis of Dox-induced cardiac toxicity[3,4]. The exact mechanisms of Dox-induced cardiac toxicity remain unclear. The search for effective and safe agents that will reduce Dox-induced cardiac toxicity may provide a new approach for promoting Dox in clinical applications. Recent studies have shown that Ang-1 significantly promoted cardiac survival after myocardial ischemic injury and attenuated cell apoptosis[6]. The role of Ang-1 in Dox-induced myocardial apoptosis has not been investigated. We observed that Ang-1 overexpression significantly attenuated Dox-induced apoptosis in H9C2 cardiomyocytes. The mechanisms involved blunting Dox-activated Fasmediated apoptotic signaling pathway and activation of the pro-survival Akt signaling pathway
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