TY - JOUR
T1 - Vascular endothelial toxicity induced by HIV protease inhibitor
T2 - Evidence of oxidant-related dysfunction and apoptosis
AU - Baliga, Reshma S.
AU - Liu, Cynthia
AU - Hoyt, Dale G.
AU - Chaves, Alysia A.
AU - Bauer, John Anthony
PY - 2004
Y1 - 2004
N2 - 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.
AB - 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.
KW - Antioxidants
KW - Apoptosis
KW - Endothelium
KW - HIV protease inhibitors
KW - Reactive oxygen species
KW - Saquinavir
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U2 - 10.1385/CT:4:2:199
DO - 10.1385/CT:4:2:199
M3 - Article
C2 - 15371635
AN - SCOPUS:4744359950
SN - 1530-7905
VL - 4
SP - 199
EP - 206
JO - Cardiovascular Toxicology
JF - Cardiovascular Toxicology
IS - 2
ER -