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Vascular endothelial toxicity induced by HIV protease inhibitor

Evidence of oxidant-related dysfunction and apoptosis

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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 μM, 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 and Affiliations

  1. Department of Pharmacology, College of Pharmacy, Ohio State University, Columbus, OH

    Reshma S. Baliga, Cynthia Liu, Dale G. Hoyt & John A. Bauer

  2. Center for Cardiovascular Medicine, Columbus Children's Research Institute, 700 Children's Drive, 43205, Columbus, OH

    Reshma S. Baliga, Alysia A. Chaves & John A. Bauer

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  1. Reshma S. Baliga
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  2. Cynthia Liu
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Correspondence to John A. Bauer.

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Baliga, R.S., Liu, C., Hoyt, D.G. et al. Vascular endothelial toxicity induced by HIV protease inhibitor. Cardiovasc Toxicol 4, 199–206 (2004). https://doi.org/10.1385/CT:4:2:199

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  • DOI: https://doi.org/10.1385/CT:4:2:199

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