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Role of Glutathione S-Transferase P in Heart Failure

谷胱甘肽 S-转移酶 P 在心力衰竭中的作用

基本信息

批准号：
8423348
负责人：
Sumanth D Prabhu
金额：
$ 34.52万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-02-01 至 2015-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8423348
关键词：
4 hydroxynonenal Ablation Accounting Acrolein Affect Aldehydes Alleles Angiogenic Proteins Anti-Inflammatory Agents Anti-inflammatory Antioxidants Apoptosis Biological Markers Bone Marrow Cardiac Cardiomyopathies Cell physiology Chronic Clinical Clinical Trials Coronary Depressed mood Diagnostic Disease Disease susceptibility Drug Metabolic Detoxication Enzymes Failure Fibrosis Functional disorder GSTP1 gene Gene Expression Generations Genetic Genetic Polymorphism Glutathione Glutathione S-Transferase Glutathione S-Transferase P Goals Heart Heart failure Hematopoietic Human Hydrogen Peroxide Individual Differences Infarction Inflammation Inflammatory Injury Isotope Labeling Left Ventricular Remodeling Ligation Lipid Peroxidation Lipid Peroxides Malignant Neoplasms Mass Spectrum Analysis Measures Membrane Metabolic Metabolism Modeling Mus Muscle Cells Myeloproliferation Myocardial Myocardium N-terminal Oxidants Oxidation-Reduction Oxidative Stress Patients Peroxidases Peroxides Phosphotransferases Play Predisposition Process Property Protein Isoforms Proteins Reactive Oxygen Species Role Selenium Stem cells Stress Systemic disease Testing Therapeutic Tissues Transgenic Mice Transgenic Organisms Variant Wild Type Mouse Work Xenobiotics adduct antioxidant therapy base biological adaptation to stress cardiac repair chemotherapy cytotoxic design gain of function in vivo neovascularization novel overexpression peroxiredoxin public health relevance regenerative therapy response stress-activated protein kinase 1

项目摘要

DESCRIPTION (provided by applicant): Although oxidative stress is a hallmark of heart failure (HF), clinical trials with antioxidants targeting first generation reactive oxygen species (ROS) such as O2/ and H2O2 have not yielded compelling benefits. However, ROS also generate secondary intermediates derived from lipid peroxidation, including peroxides and aldehydes that amplify oxidative injury. Glutathione S-transferases (GSTs) metabolize aldehydes by catalyzing their conjugation with glutathione (GSH). Select GST isoforms also have important non-catalytic functions such as physical interactions with c-Jun N-terminal kinase (JNK) that are modulated by oxidative stress. Although GSTs play a vital role in oxidative stress responses, how GSTs impact HF is unknown. Our goal is to define the functional role of GSTP, most abundant cardiac GST isoform, in HF. Our preliminary studies indicate that GSTP is downregulated in HF, and that GSTP deficiency worsens cardiac remodeling, augments protein- aldehyde adducts, depresses circulating endothelial progenitor cells (EPCs), and impairs neovascularization. Our central hypothesis, therefore, is that GSTP is a critical cardioprotective protein in post-infarction HF that ameliorates remodeling and promotes cardiac repair. To test this hypothesis, we will perform three Specific Aims. In Aim 1, we will define the role of GSTP, and the human GSTP variants hGSTP1*A and hGSTP1*C, in HF by examining post-infarction LV remodeling in wild-type (WT), GSTP-/-, and cardiac-specific hGSTP1*A and hGSTP1*C transgenic (Tg) mice. We will evaluate apoptosis, fibrosis, and inflammation together with glutathione levels, protein-adducted aldehydes, and JNK activation in the heart. In Aim 2, we will determine the metabolic contribution of GSTP to the detoxification of lipid peroxidation products in the failing heart. In isolated, perfused sham-operated and failing hearts from WT, GSTP-/- and hGSTP Tg mice, using isotope labeling and mass spectrometry, we will characterize the metabolism and detoxification of unsaturated aldehydes. In tissue homogenates, we will also determine GSTP-related peroxidase activity and levels of aldehydes and lipid peroxides. In Aim 3, we will delineate the cardiac and bone marrow (BM)-related effects by which GTSP modulates neovascularization in the failing heart. We will first determine EPC and BM progenitor cell function in WT and GSTP -/- mice, both with and without concomitant JNK inhibition. Next, we will define how GSTP ablation and hGSTP overexpression affect neovascularization and angiogenic gene expression in the sham and failing hearts from Aim 1. Lastly, we will evaluate post-infarction remodeling, inflammation, EPC mobilization, and neovascularization in chimeric mice: WT mice with GSTP-/- BM and GSTP-/- mice with WT BM. These studies will establish the role of myocardium-localized versus BM-localized GSTP in the process of remodeling, neovascularization, and inflammation in the failing heart. Collectively, this work will establish a novel paradigm of GSTP as an essential antioxidant, anti-inflammatory, and pro-angiogenic protein in HF. This model can have important diagnostic and therapeutic implications for HF patients with regard to oxidant injury.

描述(申请人提供)：尽管氧化应激是心力衰竭(HF)的一个标志，但针对第一代活性氧物种(ROS)的抗氧化剂(如O2/和H2O2)的临床试验尚未产生令人信服的好处。然而，ROS也会产生源于脂质过氧化的第二中间体，包括放大氧化损伤的过氧化物质和醛。谷胱甘肽S转移酶(GSTs)通过催化醛与谷胱甘肽的结合来代谢醛。部分GST异构体还具有重要的非催化功能，如与c-jun氨基末端激酶(JNK)的物理相互作用，这是受氧化应激调节的。虽然GST在氧化应激反应中起着至关重要的作用，但GST如何影响HF尚不清楚。我们的目标是确定GSTP在心力衰竭中的功能作用，GSTP是心脏中含量最丰富的GST亚型。我们的初步研究表明，GSTP在HF中下调，GSTP缺乏会加剧心脏重构，增加蛋白醛加合物，抑制循环内皮祖细胞(EPC)，并损害新生血管。因此，我们的中心假设是，GSTP是梗死后心力衰竭中的一种关键的心脏保护蛋白，它可以改善重构并促进心脏修复。为了验证这一假设，我们将实现三个具体目标。在目标1中，我们将通过检测野生型(WT)、GSTP-/-和心脏特异性hGSTP1*A和hGSTP1*C转基因(TG)小鼠梗死后左室重构来确定GSTP和人类GSTP变异体hGSTP1*A和hGSTP1*C在心力衰竭中的作用。我们将评估心脏中的细胞凋亡、纤维化和炎症，以及谷胱甘肽水平、蛋白加成醛和JNK活性。在目标2中，我们将确定GSTP在衰竭心脏中对脂质过氧化产物解毒的代谢贡献。在来自WT、GSTP-/-和hGSTP-/-和hGSTP-/-和hGSTP-/-的离体、灌流假手术和衰竭小鼠的心脏上，我们将使用同位素标记和质谱仪来表征不饱和醛的代谢和解毒。在组织匀浆中，我们还将测定GSTP相关的过氧化物酶活性以及醛和过氧化脂质的水平。在目标3中，我们将描述GTSP调节衰竭心脏新生血管的心脏和骨髓(BM)相关效应。我们将首先在WT和GSTP-/-小鼠中检测EPC和BM祖细胞功能，包括伴随和不伴随JNK抑制。接下来，我们将从目标1开始定义GSTP消融和hGSTP过表达如何影响假心脏和衰竭心脏中新生血管和血管生成基因的表达。最后，我们将评估嵌合小鼠：GSTP-/-BM和GSTP-/-小鼠的梗死后重塑、炎症、EPC动员和新生血管。这些研究将确定心肌定位的GSTP与骨髓定位的GSTP在衰竭心脏重塑、新生血管和炎症过程中的作用。总而言之，这项工作将建立一种新的GSTP范例，作为HF中一种基本的抗氧化剂、抗炎和促血管生成蛋白。该模型对心力衰竭患者的氧化损伤具有重要的诊断和治疗意义。