Abstract |
HIV-protease inhibitor (HIV-PI) drugs are critical for highly active antiretroviral therapy ( HAART) efficacy, but several recent reports have suggested that metabolic and/or cardiovascular toxicities are associated with these drugs. Given the importance of the HIV-PI drug class and the widespread and chronic use of these agents in an expanding patient population, further understanding of this potential drug toxicity is imperative. Here, we investigated a role for direct endothelial toxicity induced by saquinavir (SAQ), the first HIV-PI drug marketed in the United States and still an important component of HAART therapies. In initial studies using isolated vascular tissues, we observed selective impairment of endothelium-dependent vasodilation with no effect on contractile responses. Subsequent studies using human endothelial cells in culture at clinically relevant concentrations (5 and 10 microM, 2-48 h) demonstrated concentration-dependent increases in cell death, mainly via apoptosis rather than necrosis (determined via Annexin-V positive membrane labeling). Live cell imaging also demonstrated increased intracellular oxidant production (as measured by DCF fluorescence), which could be abrogated by incubation with the antioxidant N-acetylcysteine (NAC). NAC also prevented SAQ- induced apoptotic cell death. These data demonstrate that SAQ has direct toxicological effects on endothelial cells, and that the toxicity apparently involves apoptotic pathway activation via reactive oxygen and/or nitrogen species.
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Authors | Reshma S Baliga, Cynthia Liu, Dale G Hoyt, Alysia A Chaves, John A Bauer |
Journal | Cardiovascular toxicology
(Cardiovasc Toxicol)
Vol. 4
Issue 2
Pg. 199-206
( 2004)
ISSN: 1530-7905 [Print] United States |
PMID | 15371635
(Publication Type: Journal Article)
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Chemical References |
- HIV Protease Inhibitors
- Reactive Oxygen Species
- Saquinavir
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Topics |
- Animals
- Aorta, Thoracic
(drug effects, physiology)
- Apoptosis
- Cell Line
- Cell Survival
(drug effects)
- Endothelial Cells
(cytology, drug effects)
- Endothelium, Vascular
(cytology, drug effects, physiology)
- HIV Protease Inhibitors
(toxicity)
- Humans
- In Vitro Techniques
- Male
- Necrosis
- Rats
- Rats, Sprague-Dawley
- Reactive Oxygen Species
(metabolism)
- Saquinavir
(toxicity)
- Umbilical Veins
- Vasodilation
(drug effects)
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