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Selenium, Glutathione Peroxidase-1, and Homocysteine-induced Cardiac Remodeling

硒、谷胱甘肽过氧化物酶 1 和同型半胱氨酸诱导的心脏重塑

基本信息

批准号：
7470473
负责人：
Jacob Joseph
金额：
$ 24.98万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
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：
2008-04-01 至 2010-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7470473
关键词：
Address Affect Andro-Diane Animals Antioxidants Apoptosis Attenuated Biochemical Biochemistry Biological Assay Blood Blood Vessels Cardiac Cardiac Myocytes Cardiovascular Diseases Cardiovascular system Cell Proliferation Cells Cessation of life Clinical Collagen Condition Coronary Coupled Data Diastolic heart failure Diet Dietary Selenium Endothelium Enzyme Activation Enzymes Epidemic Epidemiologic Studies Erythrocytes Exposure to F2-Isoprostanes Female Fibroblasts Fibrosis Fluorescence Functional disorder Future General Population Generations Glutathione Disulfide Goals Heart Heart failure Homocysteine Homocystine Hyperhomocysteinemia Hypertrophy Incidence Intake Investigation Knowledge Laboratories Lead Link Lipid Peroxidation Matrix Metalloproteinases Measures Mediating Metabolism Mitogen-Activated Protein Kinase Inhibitor Mitogen-Activated Protein Kinases Modeling Molecular Mus Myocardial Myocardium Myofibroblast Older Population Oxidants Oxidases Oxidation-Reduction Pathology Phenotype Plasma Play Positioning Attribute Preventive Production Protein Overexpression Proteins Publishing Reactive Oxygen Species Regulation Reporting Research Risk Risk Factors Role Selenium Signal Transduction Signal Transduction Pathway Smooth Muscle Myocytes Stress Supplementation System Techniques Testing Tissue Inhibitor of Metalloproteinases Translational Regulation United States Vascular Smooth Muscle Week arteriole base cell type design dietary supplements glutathione peroxidase human MAPK14 protein in vitro Model in vivo indexing inhibitor/antagonist male mast cell mouse model novel novel strategies prevent research study selenium deficiency selenoprotein thioredoxin reductase thioredoxin reductase 1 vitamin therapy

项目摘要

DESCRIPTION (provided by applicant): Hyperhomocysteinemia (Hhe) is an independent risk factor for both systolic and diastolic heart failure. Data from our laboratory demonstrate that Hhe leads to myocardial fibrosis and diastolic dysfunction. Diastolic dysfunction and Hhe are more prevalent in the rapidly increasing older population. Hence, it is crucial to understand the mechanisms involved in Hhe's effects on the myocardium, so that it will be possible to devise appropriate preventive and treatment strategies to combat the epidemic of heart failure. Our preliminary data strongly suggest that Hhe acts via increased oxidant stress in cardiac fibroblasts to cause myocardial fibrosis and diastolic dysfunction. Dietary selenium is a potential major modulator of Hhe-induced myocardial fibrosis, since a major cellular defense against oxidant stress is the selenium requiring enzyme glutathione peroxidase- 1 (GPx-1). Based on our preliminary observations, homocysteine decreases GPx-1 activity and increases oxidant stress and collagen secretion in cultured cardiac fibroblasts, and selenium prevents these effects. The proposed project will test the central hypothesis that selenium modulates Hhe-induced myocardial oxidant stress and fibrosis by altering GPx-1 activity. We will address this central hypothesis through three Specific Aims. First, we will determine the extent to which Hhe-induced myocardial fibrosis is modulated by GPx-1, utilizing male and female mouse models that demonstrate markedly reduced, normal and increased expression of GPx-1 and treated with our well characterized dietary model of Hhe. Plasma and myocardial markers of oxidant stress, expression and activity of GPx-1 and other enzymes involved in the regulation of oxidant levels, myocardial collagen expression, as well as changes in cardiomyocytes, mast cells, vascular smooth muscle cells and endothelium will be measured. Based on our preliminary data, we will also examine for activation of the p38 mitogen activated protein kinase (MAPK) system as the main signal transduction pathway linking Hhe-induced oxidant stress to myocardial fibrosis. Second, we will determine the extent to which selenium modulates Hhe-induced myocardial fibrosis via altered GPx-1 activity. The same mouse models utilized in the first aim will be treated with diets that will create Hhe combined with deficient or excess dietary selenium. Third, we will determine if selenium modulates homocysteine's profibrotic effects by altering GPx-1 activity in cardiac fibroblasts. We will isolate cardiac fibroblasts from the mouse models with varying GPx-1 expression described above and will then study oxidant stress, expression and activity of GPx-1 and other pro- and anti-oxidant enzymes, activation of p38MAPK, and collagen metabolism, after exposure to varying levels of homocysteine and selenium. The applicant's expertise with Hhe-induced myocardial fibrosis and dysfunction, coupled with strong support from the laboratories of Dr. Joseph Loscalzo, a world renowned expert on Hhe, oxidant stress and cardiovascular disease, and Dr. Diane Handy, an expert on the biochemistry of selenium and GPx-1, positions us uniquely to conduct the proposed research. RELEVENCE: A high blood homocysteine level is widely prevalent in the general population and is a potential major contributor to the heart failure epidemic in the United States. Our proposal examines the hypothesis that dietary selenium intake, by enhancing anti- oxidant protective mechanisms in the heart, could be a powerful modulator of heart failure induced by high homocysteine levels. The results of these investigations could lead to novel preventive and treatment strategies to reduce the burden of heart failure in the Unites States.

描述（由申请人提供）：高同型半胱氨酸血症（Hhe）是收缩性和舒张性心力衰竭的独立风险因素。我们实验室的数据表明Hhe导致心肌纤维化和舒张功能障碍。舒张功能障碍和Hhe在快速增加的老年人群中更为普遍。因此，了解Hhe对心肌的影响所涉及的机制至关重要，以便有可能制定适当的预防和治疗策略来对抗心力衰竭的流行。我们的初步数据有力地表明，Hhe通过增加心脏成纤维细胞中的氧化应激而引起心肌纤维化和舒张功能障碍。膳食硒是HHE诱导的心肌纤维化的潜在主要调节剂，因为对抗氧化应激的主要细胞防御是硒需要酶谷胱甘肽过氧化物酶-1（GPx-1）。根据我们的初步观察，同型半胱氨酸降低GPx-1活性，增加氧化应激和胶原蛋白分泌在培养的心脏成纤维细胞，硒防止这些影响。该项目将测试硒通过改变GPx-1活性来调节HHE诱导的心肌氧化应激和纤维化的中心假设。我们将通过三个具体目标来解决这个中心假设。首先，我们将确定Hhe诱导的心肌纤维化在多大程度上受到GPx-1的调节，利用雄性和雌性小鼠模型，这些小鼠模型显示GPx-1的表达显著降低、正常和增加，并用我们充分表征的Hhe饮食模型进行治疗。将测量氧化应激的血浆和心肌标志物、GPx-1和参与氧化水平调节的其他酶的表达和活性、心肌胶原蛋白表达以及心肌细胞、肥大细胞、血管平滑肌细胞和内皮的变化。基于我们的初步数据，我们还将研究p38丝裂原活化蛋白激酶（MAPK）系统的激活作为连接HHE诱导的氧化应激心肌纤维化的主要信号转导途径。其次，我们将确定硒通过改变GPx-1活性调节HHE诱导的心肌纤维化的程度。在第一个目标中使用的相同小鼠模型将用将产生与缺乏或过量膳食硒组合的Hhe的膳食处理。第三，我们将确定硒是否通过改变GPx-1在心脏成纤维细胞中的活性来调节同型半胱氨酸的促纤维化作用。我们将从具有上述不同GPx-1表达的小鼠模型中分离心脏成纤维细胞，然后将研究暴露于不同水平的同型半胱氨酸和硒后的氧化应激、GPx-1和其他促氧化酶和抗氧化酶的表达和活性、p38 MAPK的活化和胶原代谢。申请人在Hhe诱导的心肌纤维化和功能障碍方面的专业知识，加上世界知名的Hhe、氧化应激和心血管疾病专家Joseph Loscalzo博士和硒和GPx-1生物化学专家Diane Handy博士实验室的大力支持，使我们能够独特地进行拟议的研究。释放：高血同型半胱氨酸水平在一般人群中广泛流行，并且是美国心力衰竭流行病的潜在主要贡献者。我们的建议检验了这样一种假设，即膳食硒摄入通过增强心脏中的抗氧化保护机制，可能是高同型半胱氨酸水平诱导的心力衰竭的有力调节剂。这些研究的结果可能会导致新的预防和治疗策略，以减少美国心力衰竭的负担。