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Danyang Ren,Quan Zhu,Jiantao Li,Tuanzhu Ha,Xiaohui Wang,Yuehua Li.Journal of Biomedical Research,2012,26(6):432-438
Overexpression of angiopoietin-1 reduces doxorubicin-inducedapoptosis in cardiomyocytes
Received: January 16, 2012  
DOI:10.7555/JBR.26.20120006
Keywordscardiomyocyte; doxorubicin; apoptosis; angiopoietin-1; phosphoinositide-3 kinase (PI3K); nuclear factor-kappaB (NF-κB)
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Danyang Ren Department of Pathophysiology, Nanjing Medical University, Nanjing, Jiangsu 210029, China 
Quan Zhu Department of Thoracic & Cardiovascular Surgery, the First Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu 210029, China 
Jiantao Li Department of Pathophysiology, Nanjing Medical University, Nanjing, Jiangsu 210029, China 
Tuanzhu Ha Department of Surgery, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA 
Xiaohui Wang Department of Surgery, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA 
Yuehua Li Department of Pathophysiology, Nanjing Medical University, Nanjing, Jiangsu 210029, China 
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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 increases 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.
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