HIV protease inhibitor ritonavir induces cytotoxicity of human endothelial cells.
OBJECTIVE
Although HIV protease inhibitors have been successfully used against HIV infection, many metabolic side effects and premature cardiovascular diseases are often associated with this therapy. The mechanisms of these complications are not clear. In this study, we investigated the effect of the HIV protease inhibitor ritonavir on human endothelial cell cultures.


RESULTS
By using nonradioactive cell proliferation and cytotoxicity assays, human endothelial cells treated with ritonavir showed a significant decrease in cell viability and an increase in cytotoxicity in a time- and dose-dependent fashion. Mitochondrial DNA was also substantially damaged with ritonavir treatment by long polymerase chain reaction analysis. In contrast, ritonavir had a very limited effect on endothelial apoptosis, as assessed by analyses of DNA fragmentation and cellular caspase-3 activity.


CONCLUSIONS
These data demonstrate, for the first time, that the HIV protease inhibitor ritonavir at concentrations near clinical plasma levels is able to directly cause endothelial mitochondrial DNA damage and cell death mainly through necrosis pathways but not through apoptosis. This study suggests that HIV protease inhibitor-mediated endothelial injury may contribute to its cardiovascular complications.
Zhong
Dian-sheng
DS
Winship Cancer Institute, Emory University, Atlanta, Ga, USA.
Lu
Xiang-huai
XH
Conklin
Brian S
BS
Lin
Peter H
PH
Lumsden
Alan B
AB
Yao
Qizhi
Q
Chen
Changyi
C
D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002461:Cell Line, Transformed; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004249:DNA Damage / Q000187:drug effects; D053938:DNA Fragmentation / Q000187:drug effects; D004272:DNA, Mitochondrial / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D017320:HIV Protease Inhibitors / Q000009:adverse effects*; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D019438:Ritonavir / Q000009:adverse effects*; D012867:Skin / Q000098:blood supply
D061945:Caspase Inhibitors; D004272:DNA, Mitochondrial; D017320:HIV Protease Inhibitors; D007770:L-Lactate Dehydrogenase; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D019438:Ritonavir