Angiopoietin-1 inhibits doxorubicin-induced human umbilical vein endothelial cell death by modulating fas expression and via the PI3K/Akt pathway.
Angiopoietin-1 (Ang-1) is essential for the maturation of blood vessels during vasculogenesis. Besides angiogenesis, recent publications indicate that Ang-1 is also a potent survival factor for endothelial cells; however, the mechanisms by which pathways remain elusive. Doxorubicin (DOX) is a powerful anticancer drug, but its use is severely restricted by its cardiotoxicity. The authors report here that Ang-1 inhibits DOX-induced cell death in human umbilical vein endothelial cells (HUVECs). Interestingly, the DOX-induced up-regulation in Fas (CD95/APO-1) and Fas ligand expression could be blocked by Ang-1, indicating a pivotal role of Ang-1 in DOX-induced Fas and Fas ligand expression. In addition, the prevention of cell death in this model system seems to be dependent on the activation of phosphatidylinositol 3-kinase (PI3K)/Akt, as Ang-1 fails to inhibit DOX-induced cell death while PI3K/Akt pathway was blocked by the PI3K inhibitor LY294002. Moreover, Ang-1 inhibits DOX-induced up-regulation of p53 through PI3K/Akt. Therefore, Ang-1 is a potent inhibitor for DOX-induced cell death through Fas and PI3K/Akt-mediated pathways.
Yin
Deling
D
Department of Internal Medicine, East Tennessee State University, Johnson City, Tennessee 37614, USA. yin@mail.etsu.edu
Li
Chuanfu
C
Kao
Race L
RL
Ha
Tuanzhu
T
Krishnaswamy
Guha
G
Fitzgerald
Matthew
M
Stuart
Charles A
CA
D042683:Angiopoietin-1 / Q000494:pharmacology*; D000903:Antibiotics, Antineoplastic / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects*; D004317:Doxorubicin / Q000633:toxicity; D004730:Endothelium, Vascular / Q000187:drug effects*; D053222:Fas Ligand Protein; D006801:Humans; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D018124:Receptors, Tumor Necrosis Factor; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014471:Umbilical Veins / Q000187:drug effects; D015854:Up-Regulation; D019014:fas Receptor / Q000096:biosynthesis / Q000235:genetics*
D042683:Angiopoietin-1; D000903:Antibiotics, Antineoplastic; D004317:Doxorubicin; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D018124:Receptors, Tumor Necrosis Factor; D016159:Tumor Suppressor Protein p53; D019014:fas Receptor; C491901:FAS protein, human; C505661:FASLG protein, human; C494918:AKT1 protein, human