title: Impact of darunavir, atazanavir and lopinavir boosted with ritonavir on cultured human endothelial cells: beneficial effect of pravastatin.
abstract: BACKGROUND
  HIV-infected patients administered long-term ritonavir-boosted protease inhibitors (PIs) are at a greater risk for developing cardiovascular diseases. Endothelial dysfunction is an initiating event in HIV-associated atherosclerosis. Cultured endothelial cells can be used as a model to compare the endothelial toxicity of different PIs.
  
  
  METHODS
  We compared the effect of darunavir (DRV), darunavir/ritonavir (DRV/r), lopinavir/ritonavir (LPV/r) and atazanavir/ritonavir (ATV/r), used at clinically relevant concentrations, on human coronary artery endothelial cell vascular function, oxidative stress, inflammation and senescence, and studied the effect of pravastatin on PI-induced alterations.
  
  
  RESULTS
  Vascular endothelial cell function, evaluated by the expression of endothelial nitric oxide synthase and the production of nitric oxide and endothelin-1, was unaffected by DRV or DRV/r, but altered by LPV/r or ATV/r. DRV or DRV/r did not alter, or mildly induced oxidative stress and inflammation (phosphorylation of p65/RelA-NFκB, secretion of IL-6 and IL-8), while ATV/r and LPV/r induced a marked increase. Secretion of sICAM or sVCAM, indicative of altered cell integrity, was not or weakly altered by DRV or DRV/r, but increased by 2-3-fold by LPV/r or ATV/r. Similar results were observed regarding senescence markers: SA-β-galactosidase activation and overexpression of phospho-p53, p16(ink4), p21(WAF-1) and prelamin A. Pravastatin could, in part, reverse PI-induced adverse effects.
  
  
  CONCLUSIONS
  Ritonavir-boosted PIs differentially induced vascular endothelial cell dysfunction, reactive oxygen species production, inflammation and senescence with no effect or a mild effect of DRV/r, an intermediate effect of ATV/r, and a stronger effect of LPV/r. Statins could, in part, protect the cells from PI-induced endothelial dysfunction.
authors.affiliation: INSERM, UMR_S 938, CDR Saint Antoine, F-75012, Paris, France.
authors.forename: Martine
authors.initials: M
authors.lastname: Auclair
authors.forename: Pauline
authors.initials: P
authors.lastname: Afonso
authors.forename: Emilie
authors.initials: E
authors.lastname: Capel
authors.forename: Martine
authors.initials: M
authors.lastname: Caron-Debarle
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Capeau
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology*; D000069446:Atazanavir Sulfate; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000187:drug effects; D000069454:Darunavir; D004357:Drug Synergism; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D061466:Lopinavir / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects; D017035:Pravastatin / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology*; D019438:Ritonavir / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology*
chemical_list: D019380:Anti-HIV Agents; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D009842:Oligopeptides; D011725:Pyridines; D013449:Sulfonamides; D061466:Lopinavir; D009569:Nitric Oxide; D000069446:Atazanavir Sulfate; D017035:Pravastatin; D019438:Ritonavir; D000069454:Darunavir