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Stress‐induced premature senescence as a mechanism of nucleoside reverse transcriptase inhibitor‐induced endothelial dysfunction (547.18)
Author(s) -
Glover Mitzi,
Hebert Valeria,
Xue Stephen,
Robinson Corie,
Crooks Samuel,
Anderson Joi,
Slaybaugh Kate,
Dugas Tammy
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.547.18
Subject(s) - senescence , coenzyme q10 , oxidative stress , endothelial dysfunction , zidovudine , nucleoside reverse transcriptase inhibitor , superoxide dismutase , pharmacology , mitochondrial toxicity , biology , medicine , mitochondrion , immunology , viral load , endocrinology , biochemistry , virus , antiretroviral therapy , viral disease
Nucleoside reverse transcriptase inhibitors (NRTIs) are a major component of the current combination therapy for HIV, known as highly active antiretroviral therapy (HAART). Studies have demonstrated that HAART has significantly decreased mortality and reduced viral load in HIV‐infected patients, but has also been associated with cardiovascular complications including endothelial dysfunction, an early marker of atherosclerosis. Our studies have shown that mice treated chronically with some NRTIs exhibit endothelial dysfunction, which is prevented by overexpression of the mitochondrial antioxidant manganese superoxide dismutase (MnSOD). Moreover, our in vitro data indicates that mitochondrial toxicity via oxidative stress may result in stress‐induced premature senescence (SIPS), a possible mechanism for the development of this dysfunction. In this study, human aortic endothelial cells (HAECs) were treated with NRTIs zidovudine (AZT), lamivudine (3TC), or tenofovir (TEN), through multiple passages to determine whether the drugs induce premature senescence. Cells were also cotreated with coenzyme Q10, a critical cofactor for mitochondrial electron transport, to determine whether a reduction in oxidative stress could prevent premature senescence. Senescence was assessed using population doubling, senescence‐associated β galactosidase staining, and measurement of cell cycle associated proteins, p16 and p21. Our findings indicate that oxidative stress induced by NRTIs enhances premature senescence in endothelial cells, and that the use of the antioxidant coenzyme Q10 attenuates this response.