Premature senescence of vascular cells is induced by HIV protease inhibitors: implication of prelamin A and reversion by statin.
OBJECTIVE
To determine whether and how protease inhibitors (PIs) could affect vascular aging.


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.
Lefèvre
Chloé
C
Faculté deMédecine Saint Antoine, Institut National de la Santé et de la Recherche Scientifique, Saint Antoine Research Center, Unité Mixte de Recherche S 938, Paris, France.
Auclair
Martine
M
Boccara
Franck
F
Bastard
Jean-Philippe
JP
Capeau
Jacqueline
J
Vigouroux
Corinne
C
Caron-Debarle
Martine
M
D000111:Acetylcysteine / Q000494:pharmacology; D000328:Adult; D000975:Antioxidants / Q000494:pharmacology; D016022:Case-Control Studies; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000187:drug effects*; D003331:Coronary Vessels / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000097:blood; D004359:Drug Therapy, Combination; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors / Q000378:metabolism; D015658:HIV Infections / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D017320:HIV Protease Inhibitors / Q000627:therapeutic use*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D034904:Lamin Type A; D061466:Lopinavir; D008665:Metalloporphyrins / Q000494:pharmacology; D008715:Methionine / Q000031:analogs & derivatives / Q000494:pharmacology; D008875:Middle Aged; D009687:Nuclear Proteins / Q000097:blood / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D010297:Paris; D017035:Pravastatin / Q000627:therapeutic use*; D011498:Protein Precursors / Q000097:blood / Q000378:metabolism*; D011744:Pyrimidinones / Q000627:therapeutic use*; D019438:Ritonavir / Q000627:therapeutic use*; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000097:blood
D000975:Antioxidants; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; C096856:FTI 277; D017320:HIV Protease Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D034904:Lamin Type A; D008665:Metalloporphyrins; D009687:Nuclear Proteins; D011498:Protein Precursors; D011744:Pyrimidinones; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C097284:manganese(III)-tetrakis(4-benzoic acid)porphyrin; C090764:prelamin A; D061466:Lopinavir; D008715:Methionine; D051231:Farnesyltranstransferase; D017035:Pravastatin; D019438:Ritonavir; D000111:Acetylcysteine