Atherogenic Mechanisms of Arsenic

砷的动脉粥样硬化机制

• 批准号: 8053409
• 负责人: Sanjay Srivastava
• 金额: $ 32.64万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-15 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8053409
• 关键词: Ablation; Affect; Animal Model; Animal Testing; Animals; Apolipoprotein E; Apoptosis; Arsenic; Arterial Fatty Streak; Arteriosclerosis; Asia; Asses; Atherosclerosis; Blood; Bone Marrow; Bone Marrow Transplantation; Calcium; Cardiovascular Diseases; Cardiovascular system; Carotid Atherosclerotic Disease; Cause of Death; Cell Adhesion Molecules; Cell Death; Cellularity; Cessation of life; Chemicals; Chronic; Collagen; Control Animal; Cytokine Activation; Disease; Endoplasmic Reticulum; Endothelial Cells; Epidemiologic Studies; Exposure to; Foam Cells; Foot Diseases; Genes; Genetic; Goals; Health; Human; Hypertension; Infant; Inflammation; Inflammatory; Ingestion; Knockout Mice; Laboratories; Lead; Lesion; Lipids; Macrophage Activation; Matrix Metalloproteinases; Measures; Mediating; Mitogen-Activated Protein Kinases; Modeling; Molecular; Molecular Chaperones; Mothers; Mus; Myocardial Infarction; Myocardial Ischemia; Oxidative Stress; Pathway interactions; Peripheral arterial disease; Phase; Population; Process; Production; Proteins; Risk Factors; Role; Signal Transduction; Smooth Muscle Myocytes; Staging; Stress; Stroke; Symptoms; T-Lymphocyte; Testing; Toxic effect; Vascular Endothelial Cell; Water; activating transcription factor; activating transcription factor 3; arterial lesion; atherogenesis; base; biological adaptation to stress; cardiovascular disorder risk; chemokine; cytokine; design; drinking water; endoplasmic reticulum stress; exposed human population; high risk; in vivo; macrophage; novel; prevent; protein folding; response; transcription factor

DESCRIPTION (provided by applicant): The overall goal of this project is to understand the mechanisms by which exposure to arsenic accelerates or aggravates atherosclerosis. Exposure to arsenic-contaminated water is a global problem and results in the manifestation of multiple cardiovascular symptoms including hypertension, stroke, and myocardial infarction. Increased atherosclerosis is likely to be the major underlying cause of the increased risk of cardiovascular disease in an arsenic-exposed population. Accordingly, the intent of this proposal is to understand the mechanism by which arsenic accelerates or exacerbates atherogenesis in a well-controlled animal model. On the basis of supportive preliminary evidence, our central hypothesis is that arsenic promotes atherogenic changes in endothelial cells and in macrophages by inducing endoplasmic reticulum (ER) stress, which in turn triggers the unfolded protein response (UPR). To test this hypothesis, we will: (1) delineate the contribution of ER stress and UPR to arsenic-mediated endothelial cell and macrophage activation; (2) examine the progression of atherogenesis in arsenic-exposed mice; and (3) elucidate the role of UPR in exacerbation of atherogenesis by arsenic. To accomplish these aims, we will examine whether exposure to arsenic induces ER stress and triggers UPR in endothelial cells and macrophages. We will identify which aspects of the UPR are triggered by arsenic and whether ER stress contributes to arsenic-induced activation of endothelial cells and foam cell formation. To assess how arsenic affects atherogenesis, we will examine early, intermediate, and advanced lesions for lipid accumulation, cellularity, inflammation, and oxidative stress in apoE-null mice exposed to arsenic. Bone marrow transplants from arsenic-exposed to non-exposed mice will be performed to delineate the specific contribution of macrophages to arsenic toxicity. To identify the in vivo role of UPR in arsenic toxicity, we will examine which components of ER stress and UPR are activated in the lesions of arsenic-exposed animals, and whether inhibition of the adaptive phase of UPR by deleting the ATF3 gene accelerates or treatment with chemical chaperones of protein folding inhibits lesion formation. Results of this project may lead to a better understanding of the mechanisms by which arsenic affects atherogenesis and how they could be therapeutically prevented. PUBLIC HEALTH RELEVANCE: Large sections of human population in the US as well as Asia are exposed to high levels of arsenic in drinking water. Previous epidemiological studies show that people exposed to high levels of arsenic have a higher risk of developing cardiovascular disease. Nevertheless, the mechanisms by which arsenic elevates cardiovascular disease risk are not known. This project is designed to mimic human exposures to arsenic in an animal model and test whether exposure to arsenic increases the rate and/or the extent of atherosclerotic lesion formation in atherosclerosis-prone mice. The project seeks to understand the underlying molecular mechanisms by which arsenic increases atherosclerosis; which processes are affected; and which cellular and molecular mechanisms mediate the cardiovascular toxicity of arsenic. Results obtained from this project are likely to provide novel models for testing atherogenic effects of arsenic exposure, in developing a better understanding of how arsenic worsens atherosclerosis and how the atherogenic effects of arsenic could be ameliorated and treated.

描述（由申请人提供）：该项目的总体目标是了解暴露于砷加速或加剧动脉粥样硬化的机制。接触砷污染的水是一个全球问题，导致多种心血管症状的表现，包括高血压，中风和心肌梗塞。动脉粥样硬化的增加可能是暴露于砷的人群中心血管疾病风险增加的主要根本原因。因此，该提案的目的是了解砷在良好控制的动物模型中加速或加剧动脉粥样硬化的机制。在支持性初步证据的基础上，我们的中心假设是，砷通过诱导内质网（ER）胁迫来促进内皮细胞和巨噬细胞的动脉粥样硬化变化，这反过来又触发了展开的蛋白质反应（UPR）。为了检验这一假设，我们将：（1）描述ER应力和UPR对砷介导的内皮细胞和巨噬细胞激活的贡献； （2）检查砷暴露的小鼠中动脉粥样硬化的进展； （3）阐明UPR在砷对动脉粥样硬化加剧的作用中的作用。为了实现这些目标，我们将检查暴露于砷中的急性应力并触发内皮细胞和巨噬细胞中的UPR。我们将确定UPR的哪些方面是由砷触发的，以及ER应力是否有助于砷诱导的内皮细胞激活和泡沫细胞的形成。为了评估砷如何影响动脉粥样硬化，我们将检查暴露于砷的Apoe-Null小鼠中脂质积累，细胞性，炎症和氧化应激的早期，中间和晚期病变。将进行从砷暴露于非暴露小鼠的骨髓移植，以描绘巨噬细胞对砷毒性的特定贡献。为了确定UPR在砷毒性中的体内作用，我们将检查在砷暴露动物的病变中激活哪些ER应力和UPR的组成部分，以及是否通过抑制UPR的自适应阶段来抑制ATF3基因加速度或用化学折叠式化学折叠蛋白折叠式抑制liSIn抑制liSion insion insion构成的化学伴侣。该项目的结果可能会更好地理解砷影响动脉粥样硬化以及如何治疗方法的机制。公共卫生相关性：美国和亚洲的大部分人口都暴露于饮用水中的砷。先前的流行病学研究表明，暴露于高水平的砷的人患心血管疾病的风险更高。然而，尚不清楚砷升高心血管疾病风险的机制。该项目旨在模仿动物模型中的人类对砷的暴露，并测试暴露于砷是否会增加动脉粥样硬化易动性疾病的率和/或动脉粥样硬化病变形成的速率和/或程度。该项目试图了解砷增加动脉粥样硬化的潜在分子机制。哪些过程受到影响；哪种细胞和分子机制介导了砷的心血管毒性。从该项目获得的结果可能会提供新的模型，以测试砷暴露的动脉粥样硬化作用，以更好地了解砷如何恶化动脉粥样硬化以及如何改善和治疗砷的动脉粥样硬化作用。