Abstract 17056: Telomerase Reverse Transcriptase (TERT) and Endothelial NO Synthase (eNOS) Mediate Vascular Anti-Senescent and Endothelial-Protective Effects of Physical Exercise
Background: The prevalence of cardiovascular disease increases with age. Aging on the cellular level depends on the function of telomeres and telomere-associated proteins. Physical exercise reduces cardiovascular morbidity and mortality. We studied vascular senescence and endothelial apoptosis in running vs. sedentary mice.
Methods and Results: C57/Bl6 wild-type, endothelial nitric oxide synthase (eNOS−/−) deficient and telomerase reverse transcriptase (TERT−/−) deficient mice were randomized to voluntary running or no running wheel conditions for three weeks. All groups n=6–10, values are mean±SEM. Aortic telomerase activity (telomere repeat amplification protocol) was elevated in exercised animals (303±32%) and protein expression of telomere-repeat binding factor 2 (254±35%) increased. Western blots showed a reduced expression of the senescence markers / apoptosis regulators Chk2, p16 and p53 (52±12%). These exercise-induced changes were attenuated in eNOS−/− and TERT−/− mice. Telomere fluorescence in-situ hybridization revealed that these effects were independent of acute changes in aortic telomere length. Endothelium-dependent vasodilation improved in wild-type and TERT−/− mice after 3 weeks exercise; endothelium-independent vasodilatation was comparable in all groups. Training similarly increased eNOS phosphorylation both in B6.129 wild-type and in TERT−/− mice. To test the functional relevance of these findings in-vivo, vascular oxidative stress was generated by treatment with lipopolysaccharide (LPS 120ng i.p.). Endothelial apoptosis in the aorta increased in LPS-treated animals to 690±8% of controls (hairpin oligonucleotide assay) and was markedly reduced in animals preconditioned by exercise (202±12%). This protection was reduced in TERT−/− (450±15%) and abolished in eNOS−/− mice.
Conclusions: Voluntary running upregulates telomerase activity and the expression of telomere-associated proteins in the aorta. Transgenic mouse studies show that the protective effect of exercise on LPS-induced aortic endothelial apoptosis is partially lost in TERT−/− mice and completely abolished in eNOS−/− mice, suggesting that eNOS and TERT mediate exercise-induced endothelial stress-resistance and survival.
- © 2010 by American Heart Association, Inc.