Role of Thioredoxin in the Aging Heart

硫氧还蛋白在心脏衰老中的作用

• 批准号: 6709226
• 负责人: Junichi Sadoshima
• 金额: $ 38.88万
• 依托单位: UNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-02-15 至 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6709226
• 关键词: Primates; age difference; aging; apoptosis; cardiac myocytes; cell age; cytoprotection; free radical oxygen; genetically modified animals; histology; laboratory mouse; laboratory rat; molecular pathology; myocardial ischemia /hypoxia; oxidative stress; terminal nick end labeling; thioredoxin; tissue /cell culture; transfection

DESCRIPTION (provided by applicant): Aging hearts exhibit increased cardiac myocyte apoptosis in basal conditions and in response to pathologic insults. Reactive oxygen species (ROS) play an essential role in mediating cardiac myocyte apoptosis. Thioredoxin (TRX) is a multifunctional and ubiquitously expressed 12kD protein. TRX, thioredoxin reductase and NADPH, collectively called the TRX system, operate as a powerful NADPH-dependent protein-disulfide reductase system. TRX is unique among anti-oxidants because TRX promotes cell survival through interaction with regulators of apoptosis/cell survival. However, the importance of TRX in regulation of ROS and cell survival is poorly characterized in cardiac myocytes. Our preliminary results indicate that cardiac myocyte apoptosis and the cellular content of TRX increase in aging monkey hearts. Expression of TRX is also upregulated by pathologic insults in the mouse heart. Transgenic mice with cardiac specific overexpression of dominant negative TRX exhibit increased oxidative stress in the heart and develop cardiac hypertrophy and apoptosis. These results suggest that TRX is upregulated in response to aging and pathologic insults and plays an important role in mediating cardioprotective effects in the aging heart. We hypothesized that: 1) TRX is upregulated in aging hearts in order to counteract age dependent increases in ROS. 2) Upregulation of TRX in response to pathologic insults is blunted in aging hearts, which causes increased susceptibility to pathologic insults in aging hearts. 3) Overexpression of TRX in its reduced form mediates cardioprotective effects, while TRX in its oxidized form mediates increased cell death and facilitates the histological changes seen in aged animals. In order to test our hypothesis, we will use cultured cardiac myocytes and transgenic mice harboring wild type or dominant negative TRX. We will also use the conscious monkey ischemia/reperfusion model in conjunction with adenovirus-mediated gene transfer in order to manipulate expression of TRX in the heart. Our study will lead to a better understanding of the mechanisms of cell death in aging hearts. Elucidation of anti-oxidative and cell survival effects regulated by TRX will lead to development of novel and specific strategies to reduce ROS and prevent cardiac myocyte death in aging hearts.

描述（由申请人提供）：衰老的心脏在基础条件下和对病理损伤的反应中表现出心肌细胞凋亡增加。活性氧（ROS）在介导心肌细胞凋亡中发挥重要作用。硫氧还蛋白 (TRX) 是一种多功能且普遍表达的 12kD 蛋白质。 TRX、硫氧还蛋白还原酶和 NADPH 统称为 TRX 系统，作为强大的 NADPH 依赖性蛋白质二硫键还原酶系统发挥作用。 TRX 在抗氧化剂中是独一无二的，因为 TRX 通过与细胞凋亡/细胞存活调节剂相互作用来促进细胞存活。然而，TRX 在调节 ROS 和细胞存活中的重要性在心肌细胞中却鲜为人知。我们的初步结果表明，衰老猴心脏中心肌细胞凋亡和 TRX 细胞含量增加。小鼠心脏中的病理损伤也会上调 TRX 的表达。心脏特异性过度表达显性失活 TRX 的转基因小鼠表现出心脏氧化应激增加，并出现心脏肥大和细胞凋亡。这些结果表明，TRX 因衰老和病理损伤而上调，并在介导衰老心脏的心脏保护作用中发挥重要作用。我们假设：1）TRX 在衰老的心脏中上调，以抵消年龄依赖性 ROS 的增加。 2）在衰老的心脏中，TRX对病理损伤的上调反应减弱，这导致衰老的心脏对病理损伤的敏感性增加。 3）还原形式的TRX过度表达介导心脏保护作用，而氧化形式的TRX介导细胞死亡增加并促进老年动物中观察到的组织学变化。为了检验我们的假设，我们将使用培养的心肌细胞和含有野生型或显性失活 TRX 的转基因小鼠。我们还将使用有意识的猴子缺血/再灌注模型与腺病毒介导的基因转移相结合，以操纵心脏中 TRX 的表达。我们的研究将有助于更好地了解衰老心脏中细胞死亡的机制。阐明 TRX 调节的抗氧化和细胞存活作用将导致开发新颖且具体的策略来减少 ROS 并防止衰老心脏中的心肌细胞死亡。