Cardioprotective effects of thioredoxin 1

硫氧还蛋白 1 的心脏保护作用

基本信息

批准号：
9027871
负责人：
Junichi Sadoshima
金额：
$ 53.29万
依托单位：
RBHS-NEW JERSEY MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-01-15 至 2018-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9027871
关键词：
5&apos -AMP-activated protein kinase Affect Antioxidants Attenuated C-terminal Cardiac Cardiac Myocytes Cardiovascular Diseases Catabolic Process Catabolism Catalytic Domain Cell Death Cell Survival Cell physiology Cells Consumption Cysteine Disulfides Electron Transport Electrons Extravasation Feedback Glutathione Goals Health Heart High Fat Diet Histones Hypertrophy Ischemia Mediating Metabolic stress Metabolic syndrome Mitochondria Modification Molecular Myocardial Ischemia N-terminal NADP NADPH Oxidase NOS3 gene Nuclear Oxidation-Reduction Oxidative Stress Oxidoreductase Pathway interactions Patients Play Post-Translational Protein Processing Predisposition Protein Kinase Protein-Serine-Threonine Kinases Proteins Proteomics Reaction Reactive Oxygen Species Reperfusion Therapy Role Side Signaling Molecule Site Source Stress Sulfhydryl Compounds Superoxide Dismutase System TXN gene Testing Transgenic Mice catalase clinically relevant disulfide bond electron donor functional restoration in vivo mouse model mutant novel novel strategies oxidation prevent protein protein interaction protein structure function response sensor transcription factor

项目摘要

DESCRIPTION (provided by applicant): Reduction and oxidation (Redox) are defined by the gain and loss of electrons, respectively, both of which affect the structure and function of proteins. Cardiac stress increases reactive oxygen species (ROS), which oxidize proteins, thereby affecting a wide variety of cellular functions, including hypertrophy and cell death. Thioredoxin1 (Trx1) is a 12 kD protein that protects the heart from pathological hypertrophy and ischemia/reperfusion. Trx1 interacts with intracellular signaling molecules, and reduces oxidized cysteine residues, thereby modulating their function. Our long-term goal is to identify important substrates of Trx1 in the heart and elucidate the functional significance of the regulatory effect of Trx1 in response to clinically relevant stress. In order to identify novel targets of Trx1 durin myocardial ischemia, we generated transgenic mice with cardiac specific expression of a Trx1 trap mutant. One of the proteins we identified using this system was AMP-activated protein kinase (AMPK), a serine threonine kinase. AMPK is an important sensor of energy stress and positively regulates the catabolic process to maintain the energy level. We hypothesize that AMPK is subjected to cysteine oxidation during myocardial ischemia, which negatively regulates AMPK. Trx1 is an essential co-factor of AMPK, allowing AMPK to be activated during myocardial ischemia to promote cell survival by reducing the oxidized cysteines in AMPK. AMPK and Trx1 form a positive feedback loop to stimulate one another's functions during stress. We will: 1) elucidate the molecular mechanism by which cysteine oxidation during ischemia inactivates AMPK, 2) demonstrate the role of Trx1 as an essential co-factor of AMPK during myocardial ischemia, and 3) demonstrate that AMPK and Trx1 form a positive feedback mechanism to protect the heart against ischemia, but that their function is impaired in response to consumption of a high fat diet. We will use proteomic analyses of posttranslational modifications and unique genetically altered mouse models. Our study will elucidate how posttranslational oxidative modification of cysteine residues regulates the activity of AMPK during metabolic stress and show that Trx1 is a critical co-factor of AMPK in the protection of the heart against prolonged ischemia.

描述（由申请人提供）：还原和氧化（氧化还原）分别由电子的增益和损失定义，这两者都会影响蛋白质的结构和功能。心脏应激增加了活性氧（ROS），从而氧化蛋白质，从而影响多种细胞功能，包括肥大和细胞死亡。硫氧还蛋白1（TRX1）是一种12 kD蛋白，可保护心脏免受病理肥大和缺血/再灌注。 TRX1与细胞内信号分子相互作用，并减少氧化的半胱氨酸残基，从而调节其功能。我们的长期目标是确定心脏中TRX1的重要底物，并阐明TRX1对临床相关应力的调节作用的功能意义。为了鉴定TRX1杜林心肌缺血的新靶标，我们产生了具有TRX1陷阱突变体心脏特异性表达的转基因小鼠。我们使用该系统鉴定的蛋白质之一是AMP激活的蛋白激酶（AMPK），一种丝氨酸苏氨酸激酶。 AMPK是能量应力的重要传感器，并积极调节分解代谢过程以维持能量水平。我们假设在心肌缺血期间，AMPK受到半胱氨酸氧化的影响，对AMPK进行负调节。 TRX1是AMPK的必不可少的共同因素，可以在心肌缺血期间激活AMPK，从而通过减少AMPK中的氧化半胱氨酸来促进细胞存活。 AMPK和TRX1形成一个正反馈回路，以刺激压力期间彼此的功能。我们将：1）阐明缺血期间半胱氨酸氧化使AMPK失活的分子机制，2）证明TRX1作为AMPK的必不可少的AMPK的作用，而在心肌缺血期间的作用，3）表明，AMPK和TRX1表明了对心脏的积极反馈机制，可以防止其抗病的症状，但会侵害其功能，以抗脉络性的功能。我们将使用翻译后修饰和独特的遗传改变的小鼠模型的蛋白质组学分析。我们的研究将阐明半胱氨酸残基的翻译后氧化修饰如何调节代谢应激期间AMPK的活性，并表明TRX1是AMPK的关键副因素，可保护心脏避免长期局部缺血。