Autophagy maintains vascular function through a novel glycolysis-linked pathway regulating eNOS.

自噬通过调节 eNOS 的新型糖酵解相关途径维持血管功能。

基本信息

批准号：
10166904
负责人：
John David SYMONS
金额：
$ 39.69万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10166904
关键词：
ATG3 gene Acute Adult Aging Animals Applied Genetics Arteries Attenuated Autophagocytosis Autophagosome Blood Pressure Blood Vessels Blood flow Cardiovascular Diseases Cattle Cell Adhesion Chronic Contralateral Data Defect Endothelial Cells Exercise Exposure to Friction Functional disorder Generations Genetic Genetic Models Glycolysis Health Human Impairment Inflammation Knockout Mice Limb structure Link Mediating Molecular Mus Mutant Strains Mice NOS3 gene Nitric Oxide Nitric Oxide Synthase Pathway interactions Periodicity Permeability Pharmacology Phenocopy Phenotype Phosphorylation Physiological Procedures Process Production Protein Kinase Refractory Reporting Repression Risk Factors Secondary to Signal Pathway Signal Transduction TP53 gene Testing Therapeutic Training Vascular Diseases Work age related aged aging population arterial stiffness base brachial artery cardiovascular disorder risk design exercise training extracellular functional decline genetic approach hemodynamics human subject improved in vivo mouse model new therapeutic target normal aging novel prevent response restoration sedentary shear stress treadmill training

项目摘要

SUMMARY One report indicates endothelial cell (EC) autophagy is compromised in aged humans. We showed that genetic repression of autophagy in ECs negates shear-stress induced EC nitric oxide (NO) synthase (eNOS) activation and NO generation. It is unknown whether disruption of autophagy specifically in ECs has functional relevance in vivo, and the mechanism whereby repressed EC autophagy compromises NO generation is not known. In Aim 1 we will test the hypothesis that conditional deletion of autophagy in ECs from adult mice (iecAtg3KO mice) phenocopies arterial dysfunction that is present in old mice. Further, based on compelling preliminary data, we will test the hypothesis that repressed EC autophagy in mutant mice and old mice evokes a p53- mediated block in glycolysis, leading to decreased signaling by extracellular ATP via the P2Y1-R and PKCδ to eNOS, resulting in arterial dysfunction. Aim 2 will explore the translational potential of this novel pathway in the context of human aging. In immortalized human arterial endothelial cells (HAECs) we hypothesize that genetic autophagy suppression prevents shear-stress induced purinergic signaling to eNOS. Next, this pathway will be evaluated in primary arterial ECs obtained from old (> 60 y) and adult (18-30 y) subjects before and following rhythmic handgrip exercise that elevates brachial artery shear-rate similarly in both groups. ECs will be used to quantify EC autophagy, eNOS activation, and NO generation. Importantly, pharmacological and genetic approaches that restore purinergic mediated signaling to eNOS will be used in these models of genetic and aging-associated autophagy repression in human ECs. Aim 3 will use adult and aged mutant mice to determine whether exercise-training attenuates the aging-associated decline in EC autophagy, and whether intact autophagy is required for training-induced vascular improvements. To evaluate translational potential, we will discern whether one-limb rhythmic handgrip exercise training by old (> 60 y) human subjects is sufficient to elevate basal and shear-induced EC autophagy initiation, eNOS activation, and NO generation vs. the contralateral sedentary limb. Results from this work have tremendous potential to reveal a new therapeutic target and approach for restoring / maintaining vascular function in the aging population.

概括一项报告表明，老年人的内皮细胞 (EC) 自噬受到损害。 EC 中自噬的抑制会抵消剪切应力诱导的 EC 一氧化氮 (NO) 合酶 (eNOS) 激活目前尚不清楚 EC 中自噬的破坏是否具有功能相关性。在体内，抑制 EC 自噬损害 NO 生成的机制尚不清楚。目标 1 我们将测试以下假设：成年小鼠 EC 中自噬的条件删除（iecAtg3KO 此外，基于令人信服的初步数据，我们将测试以下假设：突变小鼠和老年小鼠中抑制 EC 自噬会引发 p53- 介导的糖酵解阻断，导致细胞外 ATP 通过 P2Y1-R 和 PKCδ 的信号传导减少 eNOS，导致动脉功能障碍，目标 2 将探索这一新途径的转化潜力。在人类衰老的背景下，我们与这种遗传作斗争。自噬抑制可防止剪切应力诱导的嘌呤能信号传导至 eNOS。在之前和之后从老年（> 60 岁）和成人（18-30 岁）受试者获得的原发动脉 EC 中进行评估两组 EC 均采用类似的有节奏的握力练习来提高肱动脉剪切率。量化 EC 自噬、eNOS 激活和 NO 生成（重要的是，药理学和遗传）。恢复嘌呤能介导的 eNOS 信号传导的方法将用于这些遗传和 Aim 3 将使用成年和老年突变小鼠来抑制人类 EC 中与衰老相关的自噬。确定运动训练是否可以减轻与衰老相关的 EC 自噬下降，以及是否完整的自噬是训练引起的血管改善所必需的，为了评估转化潜力，我们。将辨别老年（> 60岁）人类受试者的单肢有节奏的握力练习训练是否足以与对照组相比，提高基础和剪切诱导的 EC 自噬起始、eNOS 激活和 NO 生成这项工作的结果具有揭示新治疗方法的巨大潜力。恢复/维持老年人血管功能的目标和方法。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Role of (pro)renin receptor in cyclosporin A-induced nephropathy.

肾素（原）受体在环孢菌素 A 诱导的肾病中的作用。

DOI：
发表时间：
2022-04-01
期刊：
影响因子：
0
作者：
Hu, Jiajia;Tan, Yandan;Chen, Yanting;Mo, Shiqi;Hekking, Brittin;Su, Jiahui;Pu, Min;Lu, Aihua;Du, Yanhua;Symons, J David;Yang, Tianxin
通讯作者：
Yang, Tianxin

Blueberry Metabolites Attenuate Lipotoxicity-Induced Endothelial Dysfunction.

蓝莓代谢物可减轻脂毒性引起的内皮功能障碍。

DOI：
发表时间：
2018
期刊：
影响因子：
5.2
作者：
Bharat, Divya;Cavalcanti, Rafaela Ramos Mororo;Petersen, Chrissa;Begaye, Nathan;Cutler, Brett Ronald;Costa, Marcella Melo Assis;Ramos, Renata Kelly Luna Gomes;Ferreira, Marina Ramos;Li, Youyou;Bharath, Leena P;Toolson, Emma;Sebahar, Paul;Loope
通讯作者：
Loope

Treadmill training does not enhance skeletal muscle recovery following disuse atrophy in older male mice.

跑步机训练并不能增强老年雄性小鼠废用性萎缩后骨骼肌的恢复。

DOI：
发表时间：
2023
期刊：
影响因子：
0
作者：
Yee, Elena M;Hauser, Carson T;Petrocelli, Jonathan J;de Hart, Naomi M M P;Ferrara, Patrick J;Bombyck, Princess;Fennel, Zachary J;van Onselen, Lisha;Mookerjee, Sohom;Funai, Katsuhiko;Symons, J David;Drummond, Micah J
通讯作者：
Drummond, Micah J

Effect of Continuous-Flow Left Ventricular Assist Device Support on Coronary Artery Endothelial Function in Ischemic and Nonischemic Cardiomyopathy.

连续流左心室辅助装置支持对缺血性和非缺血性心肌病冠状动脉内皮功能的影响。

DOI：
发表时间：
2019
期刊：
影响因子：
0
作者：
Symons, J David;Deeter, Lance;Deeter, Nicholas;Bonn, Trevor;Cho, Jae Min;Ferrin, Peter;McCreath, Lauren;Diakos, Nikolaos A;Taleb, Iosif;Alharethi, Rami;McKellar, Stephen;Wever;Navankasattusas, Sutip;Selzman, Craig H;Fang, James
通讯作者：
Fang, James

Dietary supplementation with strawberry induces marked changes in the composition and functional potential of the gut microbiome in diabetic mice.

膳食补充草莓会导致糖尿病小鼠肠道微生物群的组成和功能潜力发生显着变化。

DOI：
10.1016/j.jnutbio.2019.01.004
发表时间：
2019-01-18
期刊：
The Journal of nutritional biochemistry
影响因子：
0
作者：
Chrissa Petersen;Umesh D. Wakh;e;e;D. Bharat;Kiana Wong;J. E. Mueller;S. Chintapalli;B. Piccolo;T. Jalili;Z. Jia;J. Symons;K. Shankar;Pon Velayutham;An;h Babu;h
通讯作者：
h