Cellular senescence in endothelial cells from atherosclerotic patients is accelerated by oxidative stress associated with cardiovascular risk factors.
Risk factors for cardiovascular diseases (CVD) increase oxidative stress, and they are proposed to hasten endothelial cell (EC) damage and dysfunction. Our objective was to elucidate the impact of chronic exposure to risk factors for CVD on senescence of EC isolated and cultured from internal mammary arterial segments of patients with severe coronary artery disease. Senescence induced by serial passages resulted in progressive telomere shortening, and short initial telomeres predicted early appearance of senescence in culture. Neither time course of senescence nor telomere length was age-dependent, suggesting that biological age, rather than chronological age, determined the dynamics. Senescence appeared earlier in patients with longer history of risk factor for CVD, and multivariate analysis suggested that hypertension hastened the onset of senescence. Risk factors for CVD override the effects of chronological aging likely by generating stress-dependent damage: senescent EC exhibited oxidative stress (increase in lipid peroxydation and caveolin-1 gene expression) and cell damage markers (loss of eNOS expression and increase in Cox2 mRNA, lower TRF1 protein level). Thus, cell senescence was triggered both by telomere-dependent and -independent pathways. In conclusion, chronic exposure to risk factors for CVD accelerated the development of endothelial senescence that could contribute to the pathogenesis of CVD.
Voghel
Guillaume
G
Department of Surgery, Research Center, Montreal Heart Institute, Université de Montréal, Montréal, Québec, Canada.
Thorin-Trescases
Nathalie
N
Farhat
Nada
N
Nguyen
Albert
A
Villeneuve
Louis
L
Mamarbachi
Aida M
AM
Fortier
Annik
A
Perrault
Louis P
LP
Carrier
Michel
M
Thorin
Eric
E
D000328:Adult; D000367:Age Factors; D000368:Aged; D015992:Body Mass Index; D002318:Cardiovascular Diseases / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D051242:Caveolin 1 / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D016922:Cellular Senescence; D003324:Coronary Artery Disease / Q000150:complications / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051545:Cyclooxygenase 1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D042783:Endothelial Cells / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D005260:Female; D006801:Humans; D006973:Hypertension / Q000150:complications / Q000473:pathology; D015227:Lipid Peroxidation; D008297:Male; D008323:Mammary Arteries / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D008875:Middle Aged; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D018384:Oxidative Stress; D012333:RNA, Messenger / Q000378:metabolism; D012307:Risk Factors; D012720:Severity of Illness Index; D012907:Smoking / Q000009:adverse effects; D016615:Telomere / Q000378:metabolism; D035321:Telomeric Repeat Binding Protein 1 / Q000378:metabolism; D013997:Time Factors
C495540:CAV1 protein, human; D051242:Caveolin 1; D012333:RNA, Messenger; D035321:Telomeric Repeat Binding Protein 1; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human