Endogenous oxidative stress prevents telomerase-dependent immortalization of human endothelial cells

• Published in: Mechanisms of ageing and development 2010-05, Vol.131 (5), p.354-363
• Main Authors: Voghel, Guillaume, Thorin-Trescases, Nathalie, Mamarbachi, Aida M., Villeneuve, Louis, Mallette, Frédérick A., Ferbeyre, Gerardo, Farhat, Nada, Perrault, Louis P., Carrier, Michel, Thorin, Eric
• Format: Article
• Language: English
• Subjects: Acetylcysteine - pharmacology; Aged; Atherosclerosis - enzymology; Atherosclerosis - physiopathology; Biological and medical sciences; Cells, Cultured; Cellular Senescence; Coronary artery disease; Cyclin-Dependent Kinase Inhibitor p16 - metabolism; Cyclin-Dependent Kinase Inhibitor p21 - metabolism; Development. Metamorphosis. Moult. Ageing; DNA Damage; Endothelial Cells - drug effects; Endothelial Cells - enzymology; Endothelium; Female; Free Radical Scavengers - pharmacology; Fundamental and applied biological sciences. Psychology; Humans; Lentivirus; Male; Middle Aged; Oxidative Stress; Risk; Telomerase; Telomerase - metabolism; Tumor Suppressor Protein p53 - metabolism; Vertebrates: anatomy and physiology, studies on body, several organs or systems
• ISSN: 0047-6374; 1872-6216
• DOI: 10.1016/j.mad.2010.04.004

With aging, oxidative stress accelerates vascular endothelial cell (EC) telomere shortening-induced senescence, and may promote atherosclerosis in humans. Our aim was to investigate whether an antioxidant treatment combined with telomerase (hTERT) over-expression would prevent senescence of EC isolated from patients with severe atherosclerosis. Cells were isolated from internal mammary arteries ( n = 11 donors), cultured until senescence with or without N-acetylcystein (NAC) and infected, or not, with a lentivirus over-expressing hTERT. Compared to control EC, hTERT-NAC cells had increased telomerase activity, longer telomeres and underwent more cell divisions. According to the donor, hTERT-NAC either delayed ( n = 5) or prevented ( n = 4) EC senescence, the latter leading to cell immortalization. Lack of cell immortalization by hTERT-NAC was accompanied by an absence of beneficial effect of NAC alone in paired EC. Accordingly, lack of EC immortalization by hTERT-NAC was associated with high endogenous susceptibility to oxidation. In EC where hTERT-NAC did not immortalize EC, p53, p21 and p16 expression increased with senescence, while oxidative-dependent DNA damage associated with senescence was not prevented. Our data suggest that irreversible oxidative stress-dependent damages associated with cardiovascular risk factors are responsible for senescence of EC from atherosclerotic patients.