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1.
Arterioscler Thromb Vasc Biol ; 38(6): 1283-1296, 2018 06.
Artículo en Inglés | MEDLINE | ID: mdl-29599138

RESUMEN

OBJECTIVE: Atherosclerosis is an age-related disease characterized by systemic oxidative stress and low-grade inflammation. The role of telomerase and telomere length in atherogenesis remains contentious. Short telomeres of peripheral leukocytes are predictive for coronary artery disease. Conversely, attenuated telomerase has been demonstrated to be protective for atherosclerosis. Hence, a potential causative role of telomerase in atherogenesis is critically debated. APPROACH AND RESULTS: In this study, we used multiple mouse models to investigate the regulation of telomerase under oxidative stress as well as its impact on atherogenesis in vitro and in vivo. Using primary lymphocytes and myeloid cell cultures, we demonstrate that cultivation under hyperoxic conditions induced oxidative stress resulting in chronic activation of CD4+ cells and significantly reduced CD4+ T-cell proliferation. The latter was telomerase dependent because oxidative stress had no effect on the proliferation of primary lymphocytes isolated from telomerase knockout mice. In contrast, myeloid cell proliferation was unaffected by oxidative stress nor reliant on telomerase. Telomerase reverse transcriptase deficiency had no effect on regulatory T-cell (Treg) numbers in vivo or suppressive function ex vivo. Adoptive transfer of telomerase reverse transcriptase-/- Tregs into Rag2-/- ApoE-/- (recombination activating gene 2/apolipoprotein E) double knockout mice demonstrated that telomerase function was not required for the ability of Tregs to protect against atherosclerosis. However, telomere length was critical for Treg function. CONCLUSIONS: Telomerase contributes to lymphocyte proliferation but plays no major role in Treg function, provided that telomere length is not critically short. We suggest that oxidative stress may contribute to atherosclerosis via suppression of telomerase and acceleration of telomere attrition in Tregs.


Asunto(s)
Aterosclerosis/enzimología , Linfocitos T CD4-Positivos/enzimología , Proliferación Celular , Activación de Linfocitos , Linfocitos T Reguladores/enzimología , Telomerasa/metabolismo , Traslado Adoptivo , Animales , Aterosclerosis/genética , Aterosclerosis/inmunología , Aterosclerosis/prevención & control , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/trasplante , Células Cultivadas , Proteínas de Unión al ADN/deficiencia , Proteínas de Unión al ADN/genética , Modelos Animales de Enfermedad , Femenino , Masculino , Ratones Noqueados , Ratones Noqueados para ApoE , Estrés Oxidativo , Transducción de Señal , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/trasplante , Telomerasa/deficiencia , Telomerasa/genética , Homeostasis del Telómero
2.
Atherosclerosis ; 236(2): 312-20, 2014 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-25127175

RESUMEN

UNLABELLED: Statins are one of the most potent drugs in delaying age-related inflammatory changes in the arterial vessel wall, slowing down the progression of atherosclerosis. Statins have also been shown to abrogate telomere-attributed cardiovascular risk. The goal of our study was to explore a potential effect of atorvastatin on telomerase activity in peripheral blood mononuclear cells (PBMCs) and T-lymphocytes (T cells). METHODS AND RESULTS: Treatment with pharmacologically relevant concentrations (0.1-0.3 µM) of atorvastatin resulted in a 6-fold increase of telomerase activity (TA) (p < 0.0001) in human and mouse PBMCs and CD4 T cells, translating into moderate proliferation of T lymphocytes. In contrast, high doses of atorvastatin (2-5 µM) or the addition of LDL cholesterol completely inhibited proliferation, thereby abrogating telomerase activity. The proliferative effect of atorvastatin was ablated by the absense of the catalytic subunit of telomerase, telomerase reverse transcriptase (TERT). Using transgenic GFP-mTert reporter mice, we observed a decrease in telomerase-positive lymphocytes from 30% to 15% during the first 5 months of age (p < 0.01). This suggests that the decrease in immune cell turnover during normal development and maturation is mirrored by a reduction in telomerase activity in lymphocytes in-vivo. CONCLUSION: Atorvastatin and cholesterol have opposing effects on telomerase in mononuclear cells and T-lymphocytes. Our study suggests a link between cholesterol metabolism and telomere-related cardiovascular risk.


Asunto(s)
Linfocitos T CD4-Positivos/efectos de los fármacos , Ácidos Heptanoicos/farmacología , Leucocitos Mononucleares/efectos de los fármacos , Activación de Linfocitos/efectos de los fármacos , Pirroles/farmacología , Telomerasa/fisiología , Animales , Atorvastatina , Linfocitos T CD4-Positivos/enzimología , Enfermedades Cardiovasculares/epidemiología , Dominio Catalítico , División Celular/efectos de los fármacos , Células Cultivadas , LDL-Colesterol/farmacología , Relación Dosis-Respuesta a Droga , Inducción Enzimática/efectos de los fármacos , Genes Reporteros , Ácidos Heptanoicos/administración & dosificación , Humanos , Leucocitos Mononucleares/enzimología , Ratones , Ratones Noqueados , Ratones Transgénicos , Pirroles/administración & dosificación , Riesgo , Telomerasa/antagonistas & inhibidores , Telomerasa/biosíntesis , Telomerasa/genética , Telómero/ultraestructura , Homeostasis del Telómero/efectos de los fármacos
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