Mechanisms for Arsenic-Induced Vascular Disease

砷诱发血管疾病的机制

• 批准号: 7809829
• 负责人: Aaron Barchowsky
• 金额: $ 74.13万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7809829
• 关键词: Affect; Albumins; Arsenic; Bacteria; Bacterial Infections; Blood; Blood Circulation; Blood Vessels; Blood capillaries; Cardiac; Cardiovascular Diseases; Cardiovascular system; Cell physiology; Cells; Chronic; Communities; Containment; Coupled; Deposition; Disease; Disease Outcome; Disease Progression; Endothelial Cells; Environmental Exposure; Etiology; Excision; Exposure to; Fatty acid glycerol esters; Fibrosis; Functional disorder; GTP-Binding Proteins; Gastrointestinal tract structure; Generations; Genomics; Genotype; Genus Cola; Glycosaminoglycans; Grant; Guanosine Triphosphate Phosphohydrolases; Health; Heart; Hepatic Mass; Hepatocyte; Human; Hyaluronan; Hypertension; Image; Knowledge; Labyrinth fenestration; Link; Lipids; Lipoproteins; Liver; Liver Failure; Liver Fibrosis; Maintenance; Measures; Mediating; Metabolic; Metabolic Diseases; Metabolism; Molecular; Mus; NADPH Oxidase; Nutrient; Obesity; Oxidants; Pathogenesis; Perivascular Fibrosis; Phenotype; Physiological; Process; Proteins; Proteomics; Publishing; Recovery; Relative (related person); Reporting; Risk; Role; Signal Transduction; Structure; Surface; Systemic disease; Toxic Environmental Substances; Translating; United States Environmental Protection Agency; United States National Institutes of Health; Vascular Diseases; Vascular remodeling; Vascularization; Viral; abdominal fat; base; capillary; drinking water; in vivo; lipid metabolism; macromolecule; microbiome; molecular pathology; novel; nutrient metabolism; public health relevance; response; scavenger receptor; small hairpin RNA; superoxide-generating NADPH oxidase; tool; toxicant; uptake; vascular bed; vector; wasting

DESCRIPTION (provided by applicant): In response to NOT-OD-09-058: NIH Announces the Availability of Recovery Act for Competitive Revision Applications; this is an application for a competitive revision to expand the scope of the aims for 5R01- ES013781-02: Mechanisms for arsenic-induced vascular disease. Chronic exposure to trivalent arsenic is well known to cause cardiovascular diseases. In the human liver, arsenic promotes vascular remodeling, portal fibrosis, and hypertension, but the molecular pathophysiology of these arsenic-induced vascular changes is unknown. More recently, arsenic exposures have been linked to metabolic, as well as cardiovascular diseases. We proposed in 5R01-ES013781-02 that arsenic effects on the highly specialized liver sinusoidal endothelial cells (LSEC) contribute to the cardiovascular pathogenesis of arsenic exposures. The aims 5R01-ES013781- 02 investigate the hypothesis that arsenic acts at the level of G-protein coupled cell signaling to increase NADPH oxidase oxidant generation that disrupts maintenance of liver sinusoidal LSEC fenestrations and suppression of capillarization, a process that limits lipid metabolism and protein scavenging functions. The Specific Aims have not changed and are to determine: I. the molecular mechanism by which arsenic causes liver sinusoidal capillarization and remodeling in intact mice; II. the role of Nox2-based NADPH oxidase generated superoxide in mediating arsenic -induced phenotypic conversion of primary murine and human LSEC; and III. if an imbalance in LSEC GTPase activity mediates arsenic-stimulated remodeling of the LSEC. These studies were limited to investigating the initiation of arsenic responses within the first two weeks of in vivo exposure. Studies published in the first year of the grant provided proof of hypothesis for original aim 2 by demonstrating that arsenic failed to remodel and capilliarize the liver vasculature in mice lacking NADPH oxidase. Additional exploratory studies demonstrated that prolonged exposure to environmentally relevant levels of arsenic in drinking water caused progressive change in the genotypes of bacteria in the colon. This revision proposes two new aims that will translate these findings to investigating the hypothesis that arsenic-stimulated LSEC dysfunction and conversion of the gut microbiome result in pathogenic loss of scavenging activity, inappropriate lipid deposition in abdominal fat, and microvessel remodeling in the liver and heart. The aims will investigate: I. investigate the hypothesis that LSEC capillarization and dysfunction caused by environmental exposure to arsenic decreases LSEC scavenging activity, increases fat deposition, and remodels cardiac microvessels; and II. investigate the impact of arsenic exposure on the gastrointestinal tract bacterial community structure and colonization profile and the role of LSEC phenotype and systemic changes on the gut microbiome. These studies will provide essential connection of the basic studies 5R01-ES013781- 02 with disease outcomes and greatly accelerate identifying the role of LSEC dysfunction and gut microbiome changes in the etiology of environmentally-derived metabolic and vascular diseases. PUBLIC HEALTH RELEVANCE: It is known that arsenic causes cardiovascular and metabolic-linked diseases in millions of people worldwide; however, the mechanisms for the health risks of chronic low level arsenic exposures are poorly understood. These studies will use human-relevant environmental arsenic exposures of intact mice and primary isolates of mouse and human cells to reveal the molecular pathology underlying arsenic-induced vascular remodeling in the liver and systemic vascular beds to define a novel mode of action through which low, chronic arsenic exposures promote vascular diseases. In addition, these studies will examine how arsenic effects on the bacterial colonies in the gastrointestinal tract influence host metabolism to influence disease progression.

描述（由申请人提供）：响应NOT-OD-09-058：NIH宣布竞争性修订申请的恢复法案可用性;这是一项竞争性修订申请，旨在扩大5 R 01-ES 013781 -02：砷诱导血管疾病的机制的目标范围。众所周知，长期接触三价砷会导致心血管疾病。在人类肝脏中，砷促进血管重塑、门静脉纤维化和高血压，但这些砷诱导的血管变化的分子病理生理学尚不清楚。最近，砷暴露与代谢和心血管疾病有关。我们在5 R 01-ES 013781 -02中提出，砷对高度特化的肝窦内皮细胞（LSEC）的影响有助于砷暴露的心血管发病机制。目的5 R 01-ES 013781 - 02研究了砷在G蛋白偶联细胞信号传导水平上起作用以增加NADPH氧化酶氧化剂生成的假设，该氧化剂生成破坏肝窦LSEC开窗的维持和毛细血管化的抑制，这是一种限制脂质代谢和蛋白质清除功能的过程。具体目标没有改变，将确定：砷引起完整小鼠肝窦毛细血管化和重塑的分子机制; II.基于Nox 2的NADPH氧化酶产生的超氧化物在介导砷诱导的原代鼠和人LSEC的表型转化中的作用;和III.如果LSEC GT3活性失衡介导砷刺激的LSEC重塑。这些研究仅限于调查体内暴露的前两周内砷反应的启动。在拨款的第一年发表的研究证明了砷不能重塑和毛细血管化缺乏NADPH氧化酶的小鼠的肝脏血管，从而为最初的目标2提供了假设的证据。其他探索性研究表明，长期暴露于饮用水中环境相关水平的砷会导致结肠细菌基因型的渐进性变化。该修订提出了两个新的目标，将这些发现转化为研究砷刺激的LSEC功能障碍和肠道微生物组的转化导致清除活性的致病性丧失，腹部脂肪中不适当的脂质沉积以及肝脏和心脏中的微血管重塑的假设。本研究的目的是探讨：一.研究由环境暴露于砷引起的LSEC毛细作用和功能障碍降低LSEC清除活性、增加脂肪沉积和重塑心脏微血管的假设;和II.研究砷暴露对胃肠道细菌群落结构和定植概况的影响，以及LSEC表型和全身变化对肠道微生物组的作用。这些研究将为基础研究5 R 01-ES 013781 - 02与疾病结局提供必要的联系，并大大加快确定LSEC功能障碍和肠道微生物组变化在环境源性代谢和血管疾病病因学中的作用。 公共卫生相关性：众所周知，砷会导致全世界数百万人患上心血管和代谢相关疾病;然而，人们对慢性低水平砷暴露的健康风险机制知之甚少。这些研究将使用人类相关的环境砷暴露完整的小鼠和小鼠和人类细胞的主要分离株，揭示砷诱导的肝脏和全身血管床血管重塑的分子病理学，以定义一种新的作用模式，通过这种模式，低，慢性砷暴露促进血管疾病。此外，这些研究将检查砷对胃肠道细菌菌落的影响如何影响宿主代谢，从而影响疾病进展。