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相关，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子。虽然受损的EDD与氧化应激和慢性低度炎症有关，但这些过程随着年龄的增长而发展的机制以及可以用来预防它们的策略尚不完全清楚。一个未被探索的假设是，随着年龄的增长，自噬的调节和/或细胞机制的损伤是血管内皮功能障碍（EDD降低）发展的基础。自噬是细胞分解受损大分子和细胞器的主要过程，可以抑制氧化应激和炎症，并与延长寿命有关。然而，其在介导年龄相关血管内皮功能障碍中的潜在作用是完全未知的。因此，本研究训练项目的目标是确定自噬在与年龄相关的血管内皮功能障碍中的作用，并建立恢复功能的干预效果。为了实现这一目标，我将使用一种新颖的综合转化实验方法，将体外、离体和体内的生化和生理（功能）观察联系起来。具体来说，我将评估细胞培养、小鼠和人类受试者中自噬和血管内皮功能的标记/调节因子的年龄相关差异。我还将研究自噬、EDD和氧化应激/炎症之间的关系。最后，我将确定一种旨在刺激自噬和恢复衰老小鼠内皮功能的干预措施的功效。这些结果将为介导血管内皮功能年龄相关性下降的机制提供新的和临床上重要的见解。

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.