Antioxidant Defense Mechanisms: Nrf2/Keap1 Signaling in Aging Heart

描述（由申请人提供）：美国老龄化管理局预计，到2050年，美国65岁及以上的人口将占20.2%，而2000年这一比例为12.4%。老龄化人口的增加是一个重大问题，因为他们容易出现多种健康并发症。抗氧化能力的年龄依赖性下降和ROS/RNS的积累是多种健康问题的主要原因，包括心血管疾病，如心脏肥厚、心肌病、心肌梗死和老年心力衰竭。我们最近的研究结果表明，运动通过核红细胞-2 p45相关因子-2 （Nrf2）增强抗氧化功能。Nrf2是一种氧化还原敏感蛋白

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.