Doxorubicin selectively suppresses mRNA expression and production of endothelin-1 in endothelial cells.
Doxorubicin (DXR) is a widely used cytostatic agent, but its administration is limited by its cardiovascular side effects. The endothelium is one of the largest organs in the human body and due to its direct contact with blood; it is exposed to the toxic effects of DXR. The aim of this study was to investigate in endothelial cells the effects of DXR on the expression of genes involved in cardiovascular diseases. We used in vitro cultured human umbilical vein endothelial cells (HUVEC) as a model; gene expression was assessed by SuperArray and qPCR. Out of the 96 representative genes of cardiovascular importance, the expression of only the ET-1 gene changed significantly. ET-1 mRNA expression was 10.9% of the untreated control (p=0.0049). This result was confirmed by qPCR (2.41% of control, p=0.0022). DXR also suppressed ET-1 production at protein level (p=0.0116). Both the early decrease in endothelial ET-1 production in the presence of DXR and the high plasma level of DXR during chemotherapy may influence the toxic effects of the drug.
Keltai
Katalin
K
Semmelweis University, 3rd Dept of Medicine, 4. Kutvolgyi u., Budapest H-1125, Hungary. keltaikati@gmail.com
Cervenak
László
L
Makó
Veronika
V
Doleschall
Zoltán
Z
Zsáry
András
A
Karádi
István
I
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology*; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D019332:Endothelin-1 / Q000096:biosynthesis* / Q000235:genetics; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D012333:RNA, Messenger / Q000096:biosynthesis*; D014471:Umbilical Veins / Q000166:cytology
D000903:Antibiotics, Antineoplastic; D019332:Endothelin-1; D012333:RNA, Messenger; D004317:Doxorubicin