ω-3多不饱和脂肪酸（ω-3 PUFAs）在预防血管衰老相关疾病方面发挥着积极作用。血管衰老始发于内皮细胞衰老，我们的预实验结果发现ω-3 PUFAs中的二十二碳六烯酸（DHA）可以延缓棕榈酸诱导的内皮细胞衰老，而其分子机制尚不清楚。SIRT1是NAD+依赖的脱乙酰基酶，可以通过增加NO产生以及清除活性氧来发挥抗细胞衰老作用。因此我们提出假说：ω-3 PUFAs可以通过抗炎、抗氧化延缓内皮细胞衰老，其机制与增加SIRT1的活性和/或表达有关。本研究将首先在细胞、分子水平探讨ω-3 PUFAs对棕榈酸诱导的内皮细胞衰老的影响，阐明SIRT1在其中的作用及分子机制；其次利用高脂诱导和内皮细胞SIRT1基因缺陷的衰老动物模型在整体动物水平上探讨SIRT1在ω-3 PUFAs抗血管衰老中的作用。本研究将为ω-3 PUFAs对内皮细胞衰老相关慢性疾病的预防提供理论基础和营养干预新策略。

Nutritional studies indicate that ω-3 polyunsaturated fatty acids (ω-3 PUFAs) are beneficial in alleviating the cardiovascular impairments associated with aging. Vascular biology studies show that vascular aging manifested by endothelial cell (EC) senescence is associated with increased oxidative and inflammatory stresses in ECs. Our preliminary experiments show that docosahexaenoic acid (DHA) exerts anti-inflammatory and anti-oxidative effects in ECs, which delays the EC senescence caused by high level of palmitic acid. However, the molecular basis of such beneficial effect of DHA remains to be determined. Activation and/or increased expression of SIRT1, an NAD+-dependent deacetylase, shows a marked effect in anti-cell senescence, which is contributed by SIRT1 attenuation of reactive oxygen species and increase of eNOS-derived NO generation. Thus, our hypothesis is that ω-3 PUFAs activate and/or increase the expression of SIRT1 in ECs. As a result, ECs show an anti-senescence phenotype with increased anti-inflammatory and anti-oxidative capacity. The three Specific Aims are: (1) to investigate the effects of ω-3 PUFAs activation of SIRT1 on palmitic acid-induced EC aging; (2) to study the molecular consequences resulted from ω-3 PUFAs activation of SIRT1 in the context of SIRT1 target genes and their anti-inflammatory and anti-oxidative effects in ECs; and (3) to elucidate EC aging in C57BL/6 wild-type mice fed a high fat diet in the presence or absence ofω-3 PUFAs. The results will then be compared with that in EC-specific SIRT1 knockout (EC-SIRT1-/-) mice with the same feeding protocols. Thus, results from this study will provide new information of the beneficial effects of ω-3 PUFAs on vascular aging and nutritional intervention.