Poster Topical Area: Aging and Chronic Disease
Poster Board Number: 87
Objectives: SIRT1, an NAD+-dependent deacetylase, shows a marked effect in anti-cell senescence. Docosahexaenoic acid (DHA) is beneficial in alleviating the cardiovascular impairments. The objective of this study was to investigate whether DHA plays a role in modulating endothelial cells (ECs) senescence and endothelial dysfunction via SIRT1 in a diet-induced obesity (DIO) model.
Methods: Middle-aged male C57BL/6 mice were assigned to 5 groups (n=12 for each) and maintained for 20 weeks in total: (i) CD mice placed on a control diet (10% kcal fat); (ii) HFD mice fed a high- fat diet (60% kcal fat); (iii) HFD+DHA mice fed a HFD with DHA supplementation (100 mg/kg bw, twice a week administrated by gavage for the last 8 weeks of the experiment); The other two groups of mice (iv: HFD+DHA+Sirt1 k/d) and (v: HFD+DHA+Scr) were intravenously injected with of Sirt1 shRNA or Scr shRNA lentivirus solution semiweekly with the same treatment as the group (iii). Endothelial function was determined by wire myograph using aortic rings or ex vivo cultured aortic rings treated with different doses of DHA. In vitro, senescence was induced by exposing HUVECs to palmitic acid (PA) and quantified by senescence-associated β-galactosidase staining.
Results: In the DIO model, endothelium-dependent relaxation was impaired and inflammatory markers and superoxide level were elevated in aorta compared with CD mice. These effects were reversed by DHA in DIO SIRT1 wild-type mice but not in DIO SIRT1 k/d mice. DHA reversed the decrease the expression of senescence-associated makers and the activation of eNOS in the isolated aorta of DIO mice. These effects were partially abolished by SIRT1 knockdown. In HUVECs, DHA prevented PA-induced cell senescence and the decrease of SIRT1 level. At the molecular level, DHA prevented PA-induced the decrease of eNOS-derived NO generation and the increase of reactive oxygen species and inflammation. Inhibition of SIRT1 by sirtinol partially reversed the effect of DHA on PA-induced senescence.
Conclusions: SIRT1 plays a critical role in the inhibition of ECs senescence and endothelial dysfunction in DIO mice supplemented with DHA. This study will provide new information of the beneficial effects of DHA on endothelial dysfunction associated with vascular aging.
The study was supported by"the Fundamental Research Funds for the Central Universities" (xjj2017186)
Dept. of Medicine, Xi'an Jiaotong University
Xi’an, Shaanxi, China (People's Republic)