Oxidative Stress and Myocardial Function

氧化应激与心肌功能

基本信息

批准号：
7660269
负责人：
MARIUS P SUMANDEA
金额：
$ 6.08万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-05-15 至 2011-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7660269
关键词：
Actomyosin Adenosinetriphosphatase Affect Age Aging Angiotensin II Animals Antioxidants Area Binding Biochemical Energetics Biological Assay Cardiac Cause of Death Cells Contractile Proteins Detergents Development Disease Progression Drug Design EUK-8 Event Figs - dietary Fluorescence Free Radicals Functional disorder GTP-Binding Proteins Goals Heart Diseases Heart failure Human Hydrogen Peroxide Hydroxyl Radical Hypertension Hypertrophy Immunoblot Analysis Inbred SHR Rats Inbred WKY Rats Incidence Iron Lead Length Mass Spectrum Analysis Measures Mechanics Membrane Microfilaments Modeling Modification Molecular Muscle Cells Muscle Fibers Muscle Proteins Muscle function Myocardial Myocardium Nitric Oxide Nitric Oxide Synthase Oxidants Oxidative Stress Phosphorylation Post-Translational Protein Processing Production Proteins Rattus Research Saline Sarcomeres Signal Transduction Skin Stress Structure Superoxide Dismutase Superoxides System Testing Time Ventricular Remodeling Work base catalase cost gel electrophoresis hemodynamics inorganic phosphate mimetics morphometry normotensive oxidation papillary muscle prevent public health relevance research study senescence theories young adult

项目摘要

DESCRIPTION (provided by applicant): It is well established that cardiac contractile reserve declines while the incidence of heart failure increases dramatically with age. According to the "free radical theory of aging," cardiac dysfunction may be the result of oxidative stress-induced myocardial remodeling. Our long-term goal is to elucidate signal transduction and cellular and molecular mechanisms by which post-translational modifications of myofilament proteins, lead to alterations in cardiac muscle function and ultimately to heart failure. The hypothesis underlying this work is that oxidative stress-induced modifications of cardiac contractile proteins are exacerbated with age and cardiac disease progression, and lead to impaired myofilament function. To test this hypothesis we propose a comprehensive and versatile set of experiments using a mixture of mechano-energetic and biochemical/biophysical approaches. The proposed research will utilize the spontaneously hypertensive rat model, regarded for years as a good model for human systemic hypertension, recently demonstrated as an excellent model to study oxidative stress-associated contractile dysfunction. Our aims seek to: 1) Elucidate the oxidative stress-induced modifications of myofilament proteins in young, adult and old spontaneously hypertensive rats, compared with age matched normotensive Wistar-Kyoto rats. Experiments proposed here test the hypothesis that oxidative stress induces detectable modifications of myofilament proteins, and that aging and hemodynamic stress (hypertension) lead to distinctive levels of modifications, which may differentially modulate myofilament function. 2) Investigate the functional effects of oxidative stress with age and heart disease progression in WKY and SHR myocardium. Experiments proposed here test the hypothesis that oxidative stress-induced modifications of sarcomeric proteins alter myofilament activation and might be key determinants of cardiac dysfunction. Functional significance of oxidative stress-induced modifications will be evaluated in skinned papillary muscle fiber bundles and intact myocytes from SHR and WKY animals. Overall, these experiments will result in a better understanding of the timing and the hierarchy of cellular events leading to cardiac dysfunction during the normal myocardial senescence, and during the development of heart failure in the rat. This research could prove of paramount importance in unraveling mechanisms leading to heart failure and identifying new targets or target areas for rational drug design. PUBLIC HEALTH RELEVANCE: Heart failure the leading cause of death in the U.S. increases dramatically with age due of oxidative stress. We propose to study how age and oxidative stress modify the structure of heart muscle proteins and change function. We hope to prevent this by the use of antioxidants.

描述（由申请人提供）：众所周知，心脏收缩储备会下降，而心力衰竭的发生率随着年龄的增长而大大增加。根据“自由基衰老理论”，心脏功能障碍可能是氧化应激诱导的心肌重塑的结果。我们的长期目标是阐明信号转导以及细胞和分子机制，通过这些机制，肌丝蛋白的翻译后修饰会导致心脏肌肉功能的改变并最终导致心力衰竭。这项工作的基本假设是，随着年龄和心脏病的进展，氧化应激诱导的心脏收缩蛋白的修饰受到加剧，并导致肌膜功能受损。为了检验这一假设，我们提出了使用机械能和生化/生物物理方法的混合物进行全面且通用的实验集。拟议的研究将利用自发的高血压大鼠模型，该模型多年来被视为人类全身性高血压的良好模型，最近被证明是研究氧化氧化应激相关收缩功能障碍的出色模型。我们的目标是：1）与年龄匹配的年龄匹配的正常性Wistar-Kyoto大鼠相比，年轻，成人和老年人自发性高血压大鼠的氧化应激诱导的肌丝蛋白的修饰。这里提出的实验检验了以下假设：氧化应激诱导可检测到的肌丝蛋白的修饰，以及衰老和血液动力学应激（高血压）导致独特的修饰水平，这可能会差异地调节肌膜功能。 2）研究WKY和SHR心肌中氧化应激随年龄和心脏病进展的功能作用。这里提出的实验检验了以下假设：氧化应激诱导的肉瘤蛋白的修饰改变了肌丝的激活，可能是心脏功能障碍的关键决定因素。氧化应激引起的修饰的功能意义将在皮肤乳头肌肉纤维束和SHR和WKY动物完整的心肌细胞中进行评估。总体而言，这些实验将更好地理解细胞事件的时间和层次结构，导致正常心肌衰老期间心脏功能障碍以及大鼠心力衰竭的发展。这项研究可能证明在揭示导致心力衰竭的机制并识别出新的靶标或合理药物设计的目标领域中至关重要。公共卫生相关性：心力衰竭在美国的主要死亡原因随着氧化压力而大大增加。我们建议研究年龄和氧化应激如何改变心肌蛋白的结构和变化功能。我们希望通过使用抗氧化剂来防止这种情况。