Antioxidant Defense Mechanisms: Nrf2/Keap1 Signaling in Aging Heart

抗氧化防御机制：衰老心脏中的 Nrf2/Keap1 信号传导

基本信息

批准号：
8519208
负责人：
Rajasekaran Namakkal Soorappan
金额：
$ 7.04万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-01 至 2015-01-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): The Administration on Aging projects that by the year 2050, 20.2% of the population in the United States will be age sixty-five and older compared to 12.4% in the year 2000. This increase in the aging population is of major concern as they are prone to develop multiple health complications. Age dependent decline in antioxidant potential and accumulation of ROS/RNS are primary causes for multiple health problems, including cardiovascular diseases such as cardiac hypertrophy, cardiomyopathy, myocardial infarction and heart failure in the elderly. Our recent findings indicate that exercise escalates antioxidant function through nuclear erythroid-2 p45 related factor-2 (Nrf2). Nrf2 is a redox-sensitive protein and master transcriptional regulator of redox homeostatic genes, which facilitate the defense against oxidative stress. The Nrf2 is regulated by Kelch like ECH associated protein (Keap1), a cytosolic repressor. Studies from our laboratory reveal that acute exercise (AE; 15-20 meter/min for 50 min/day, for 2 days) induces Nrf2 nuclear translocation and promotes cytoprotective mechanisms/pathways in the heart. However, one-week recovery following the AE returns Nrf2 and its target antioxidant effects back to levels seen in control (sedentary) mice. Thus, it may necessitate more prolonged, but moderate exercise to activate Nrf2/ARE-antioxidant signaling. Importantly, abrogation of Nrf2 results in dramatic deregulation of antioxidants and oxidative stress in Nrf2-/- when compared to age matched wild-type (WT) mice upon AE. Surprisingly, the degree of susceptibility to AE was similar in aged (>24 months) WT and young Nrf2-/- when compared to young (2 months) WT mice. In addition, increased ROS levels were also observed in the hearts of aging WT, when compared to young WT mice. Of note, the aging Nrf2-/- mice exhibited oxidative stress, while the WT mice showed improved myocardial antioxidant function after 2-weeks of exercise. Interestingly, the exercised WT had increased Nrf2 nuclear translocation, when compared to age- matched sedentary WT mice. These observations emphasize the importance of enhancing the endogenous cytoprotective mechanisms to combat age-induced ROS/RNS and oxidative stress. Thus, we propose that activation of Nrf2 is essential for maintaining intracellular redox homeostasis and protecting myocardium from age-associated oxidative stress. Hither to, non-pharmacological (physical exercise) mechanisms that improve Nrf2 function in the heart have not been investigated. Based on the critical role for Nrf2 and preliminary evidence from our laboratory, we propose the following hypothesis. Hypothesis: Enhanced Nrf2/ARE signaling induced by exercise promotes antioxidant defense mechanisms and thereby prevents age-associated oxidative stress in the heart. To test this hypothesis, we propose the following aims. Specific Aim 1: To determine whether genetic knockdown of Keap1 activates Nrf2/ARE-antioxidant signaling and protects the heart from age-induced oxidative stress. Specific Aim 2: To determine whether chronic moderate exercise activates Nrf2/ARE-signaling and protects the aging heart from hypertrophy.

描述（由申请人提供）：老龄化项目的政府，到2050年，美国的人口中有20.2％的年龄将六十五岁及以上，而在2000年为12.4％。老龄化人口的这种增加是主要的关注，因为它们容易发生多种健康并发症。抗氧化潜力的年龄依赖性下降和ROS/RN的积累是多种健康问题的主要原因，包括心血管肥大，心肌病，心肌梗死和心力衰竭等心血管疾病。我们最近的发现表明，运动通过核红细胞-2 p45相关因子2（NRF2）升级抗氧化功能。 NRF2是一种对氧化还原敏感的蛋白氧化还原稳态基因的主要转录调节剂，促进防御氧化应激。 NRF2受kelch的调节，例如ECH相关蛋白（KEAP1），一种胞质抑制剂。我们实验室的研究表明，急性运动（AE; 15-20米/min/day/天，持续2天）会诱导NRF2核易位，并促进心脏中的细胞保护机制/途径。然而，AE后的一周恢复返回NRF2，其靶抗氧化作用回到对照（久坐）小鼠中的水平。因此，可能需要更延长延长但中等的运动才能激活NRF2/是抗氧化的信号传导。重要的是，与年龄相匹配的野生型（WT）小鼠相比，NRF2的废除会导致NRF2 - / - 中抗氧化剂的急剧失调和氧化应激。令人惊讶的是，与年轻（2个月）WT小鼠相比，年龄（> 24个月）的年龄（> 24个月）和年轻的NRF2 - / - 的易感程度相似。另外，与年轻的WT小鼠相比，在老化WT的心脏中也观察到ROS水平升高。值得注意的是，老化的NRF2 - / - 小鼠表现出氧化应激，而WT小鼠在运动2周后表现出改善的心肌抗氧化功能。有趣的是，与年龄匹配的久坐的WT小鼠相比，运动的WT增加了NRF2核易位。这些观察结果强调了增强内源性细胞保护机制来对抗年龄引起的ROS/RN和氧化应激的重要性。因此，我们建议NRF2的激活对于维持细胞内氧化还原稳态和保护心肌免受年龄相关氧化应激至关重要。尚未研究改善心脏NRF2功能的非药理（体育锻炼）机制。基于NRF2的关键作用和我们实验室的初步证据，我们提出了以下假设。假设：锻炼诱导的NRF2/是增强的NRF2/是抗氧化剂防御机制，从而阻止了心脏中与年龄相关的氧化应激。为了检验这一假设，我们提出以下目的。特定目的1：确定KEAP1的遗传敲低是否激活NRF2/是抗氧化剂信号，并保护心脏免受年龄诱导的氧化应激。特定目标2：确定慢性中等运动是否激活NRF2/是信号，并保护衰老的心脏免受肥大的侵害。

项目成果

期刊论文数量（16）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Differential regulation of miRNA and mRNA expression in the myocardium of Nrf2 knockout mice.

DOI：
10.1186/s12864-017-3875-3
发表时间：
2017-07-03
期刊：
BMC genomics
影响因子：
4.4
作者：
Quiles JM;Narasimhan M;Shanmugam G;Milash B;Hoidal JR;Rajasekaran NS
通讯作者：
Rajasekaran NS

Reductive potential - a savior turns stressor in protein aggregation cardiomyopathy.

DOI：
10.1016/j.bbadis.2014.11.010
发表时间：
2015-01
期刊：
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
影响因子：
6.2
作者：
Narasimhan, Madhusudhanan;Rajasekaran, Namakkal S.
通讯作者：
Rajasekaran, Namakkal S.

Maternal perinatal calorie restriction temporally regulates the hepatic autophagy and redox status in male rat.

DOI：
10.1016/j.freeradbiomed.2018.09.029
发表时间：
2019-01
期刊：
Free radical biology & medicine
影响因子：
7.4
作者：
Devarajan A;Rajasekaran NS;Valburg C;Ganapathy E;Bindra S;Freije WA
通讯作者：
Freije WA

Nrf2 deficiency promotes apoptosis and impairs PAX7/MyoD expression in aging skeletal muscle cells.

DOI：
10.1016/j.freeradbiomed.2014.02.023
发表时间：
2014-06
期刊：
FREE RADICAL BIOLOGY AND MEDICINE
影响因子：
7.4
作者：
Narasimhan, Madhusudhanan;Hong, Jennifer;Atieno, Nancy;Muthusamy, Vasanthi R.;Davidson, Christopher J.;Abu-Rmaileh, Naser;Richardson, Russell S.;Gomes, Aldrin V.;Hoidal, John R.;Rajasekaran, Namakkal S.
通讯作者：
Rajasekaran, Namakkal S.

Cardiac Aging - Benefits of Exercise, Nrf2 Activation and Antioxidant Signaling.