Premature Senescence of Vascular Cells Is Induced by HIV Protease Inhibitors

Abstract

OBJECTIVE: To determine whether and how protease inhibitors (PIs) could affect vascular aging. METHODS AND RESULTS: HIV therapy with PIs is associated with an increased risk of premature cardiovascular disease. The effect of ritonavir and a combination of lopinavir and ritonavir (for 30 days) on senescence, oxidative stress, and inflammation was evaluated in human coronary artery endothelial cells (HCAECs). These HCAECs were either cotreated or not cotreated with pravastatin or farnesyl transferase inhibitor (FTI)-277 or with 2 antioxidants (manganese [III] tetrakis [4-benzoic acid] porphyrin [MnTBAP] and N-acetyl cysteine). Senescence markers were evaluated in peripheral blood mononuclear cells (PBMCs) from HIV-infected patients under PI treatment. PIs induced senescence markers, prelamin A accumulation, oxidative stress, and inflammation in HCAECs. Senescence markers and prelamin A were also observed in PBMCs from HIV-infected patients under ritonavir-boosted PIs. Pravastatin, FTI-277, and antioxidants improved PI adverse effects in HCAECs. Senescence markers were lower in PBMCs from PI-treated patients cotreated with statins. CONCLUSIONS: PIs triggered premature senescence in endothelial cells by a mechanism involving prelamin A accumulation. Accordingly, circulating cells from HIV-infected patients receiving PI therapy expressed senescence markers and prelamin A. Statin was associated with improved senescence in endothelial cells and patient PBMCs. Thus, PIs might promote vascular senescence in HIV-infected patients; and statins might exert beneficial effects in these patients.