Vascular endothelial toxicity induced by HIV protease inhibitor: evidence of oxidant-related dysfunction and apoptosis.

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.

• 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)

Chemical References

• HIV Protease Inhibitors
• Reactive Oxygen Species
• Saquinavir

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)