Role of Autophagy in Vascular Endothelial Dysfunction with Aging

描述(由申请人提供)：衰老与血管内皮功能障碍的发展有关，其特征是内皮依赖性扩张(EDD)受损，这是心血管疾病风险的独立预测因素。尽管EDD受损与氧化应激和慢性低度炎症有关，但这些过程随年龄增长而发展的机制和预防它们的策略尚不完全清楚。一个尚未探索的假设是，自噬调节和/或细胞机制的损害是血管内皮功能障碍(EDD减少)随年龄增长而发展的基础。自噬是细胞分解受损的大分子和细胞器的主要过程，它抑制氧化应激和炎症，并与延长寿命有关。然而，它在调节与年龄相关的血管内皮功能障碍中的潜在作用是完全未知的。因此，本研究培训项目的目标是确定自噬在年龄相关性血管内皮细胞功能障碍中的作用，并建立恢复功能的干预措施的有效性。为了实现这一点，我将使用一种新的综合翻译实验方法，将体外、体外和体内的生化和生理(功能)观察联系起来。具体地说，我将评估在细胞培养、小鼠和人类受试者中自噬和血管内皮功能的标记物/调节因子与年龄相关的差异。我还将研究自噬、EDD和氧化应激/炎症之间的关系。最后，我将确定一项旨在刺激小鼠自噬并随着年龄的增长恢复内皮功能的干预措施的有效性。这些结果将为调节年龄相关性血管内皮功能下降的机制提供新的和临床上重要的见解。 公共卫生相关性：衰老与血管内皮功能障碍的发展有关，血管内皮功能障碍是心血管疾病的重要预测因子，但这一过程背后的机制尚不完全清楚。一种尚未探索的假设是，自噬的损害是随着年龄的增长血管内皮功能障碍发展的基础，自噬是一个重要的细胞“管家”过程。这项转译研究项目旨在评估自噬在细胞、小鼠和人类中与年龄相关的血管内皮细胞功能障碍中的作用，并将为相关机制和潜在的预防策略提供新的和重要的临床见解。

DESCRIPTION (provided by applicant): Aging is associated with the development of vascular endothelial dysfunction characterized by impaired endothelium-dependent dilation (EDD), an independent predictor of cardiovascular disease risk. Although impaired EDD is associated with oxidative stress and chronic low-grade inflammation, the mechanisms by which these processes develop with aging and strategies that can be employed to prevent them are incompletely understood. One unexplored hypothesis is that impairments in the regulation and/or cellular machinery of autophagy underlie the development of vascular endothelial dysfunction (reduced EDD) with aging. Autophagy, the major process by which cells catabolize damaged macromolecules and organelles, inhibits oxidative stress and inflammation and is associated with enhanced longevity. However, its potential role in mediating age-associated vascular endothelial dysfunction is entirely unknown. Accordingly, the goal of this research training project is to determine the role of autophagy in age-related vascular endothelial dysfunction, and to establish the efficacy of an intervention for restoring function. To accomplish this, I will use a novel integrative translational experimental approach that links biochemical and physiological (functional) observations in vitro, ex vivo and in vivo. Specifically, I will assess age-related differences in markers/regulators of autophagy and vascular endothelial function in cell culture, mice, and human subjects. I will also examine relations between autophagy, EDD and oxidative stress/inflammation. Finally, I will determine the efficacy of an intervention designed to stimulate autophagy and restore endothelial function with aging in mice. These results will provide novel and clinically important insight regarding the mechanisms mediating the age-related decline in vascular endothelial function. PUBLIC HEALTH RELEVANCE: Aging is associated with the development of vascular endothelial dysfunction, an important predictor of cardiovascular disease, but the mechanisms underlying this process are incompletely understood. One unexplored hypothesis is that impairments in autophagy, an important cellular "housekeeping" process, underlie the development of vascular endothelial dysfunction with aging. This translational research project is designed to assess the role of autophagy in age-related vascular endothelial dysfunction in cells, mice and humans, and it will provide novel and clinically important insight into related mechanisms and potential preventative strategies.