Role of Trimethylamine-N-oxide in endothelial dysfunction

三甲胺-N-氧化物在内皮功能障碍中的作用

基本信息

批准号：
10888738
负责人：
Sai Sudha Koka
金额：
$ 38.13万
依托单位：
TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-19 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10888738
关键词：
Abbreviations Acceleration Address Adhesions Applications Grants Arterial Fatty Streak Arteries Atherosclerosis Blood Vessels CASP1 gene Cardiovascular Diseases Cardiovascular system Carnitine Carotid Arteries Caspase Inhibitor Cathepsins B Cells Ceramides Cessation of life Choline Circulation Developed Countries Disease Disease Progression Endothelial Cells Endothelium Exposure to Fluorochrome HMGB1 gene Health Heart High Mobility Group Proteins Homing Human IL18 gene Impairment In Vitro Inflammasome Inflammation Inflammatory Inflammatory Response Interleukins Intestines Knockout Mice Knowledge Lecithin Lysosomes Macrophage Mediating Membrane Metabolic Molecular Morbidity - disease rate Multivesicular Body Mus NADPH Oxidase Nitric Oxide Nucleotides Pathogenesis Pathogenicity Patients Pattern Permeability Plasma Process Production Proteins Risk Factors Rodent Rodent Model Role Sclerosis Series Signal Pathway Signal Transduction Sphingolipids Sphingosine Superoxides T-Lymphocyte Testing Tight Junctions Transmission Electron Microscopy Vasodilation Work acid sphingomyelinase atherogenesis cardiovascular injury cardiovascular risk factor cell injury clinical development clinically relevant dietary endothelial dysfunction endothelial regeneration endothelial stem cell exosome gut microbes in vivo innovation insight marenostrin metabolomics microbial monocyte mortality new therapeutic target novel novel therapeutic intervention receptor recruit repaired response sphingosine 1-phosphate trafficking trimethyloxamine vascular inflammation vascular injury

项目摘要

Project Summary Cardiovascular diseases (CVDs) are implicated in 50% of deaths in developed countries and is thus a major health concern and we still remain far from a cure. In addition to the traditional risk factors for CVDs, the influence exerted by gut microbial metabolites on the pathogenesis of CVDs has been recognized only in recent times. Trimethylamine-N-oxide (TMAO), a gut microbe-derived metabolite of dietary phosphatidylcholine/carnitine is elevated in the circulation of CVD patients and has been associated with atherosclerosis and CVD progression in rodents and humans. The present grant proposal attempts to define novel molecular signaling mechanisms mediating the responses of arterial endothelial cells (ECs) to TMAO, which will provide new insights into the pathogenesis of endothelial dysfunction and vascular injury associated with atherosclerosis. Our preliminary results have shown that TMAO induced Nlrp3 inflammasomes have direct actions on the endothelial cells. Thus TMAO induces both inflammatory and non-inflammatory effects leading to endothelial dysfunction and ultimately atherosclerosis. These represents novel pathogenic mechanisms of TMAO beyond inflammation. Based on these observations, we hypothesize that gut microbial metabolites such as TMAO which are released into the circulation act as endogenous danger signals and induce both inflammatory and non-inflammatory responses leading to endothelial dysfunction and vascular injury which consequently manifests into atherogenesis in the arterial wall. To test this hypothesis, we will address how TMAO induces endothelial dysfunction and atherosclerosis in in vivo using Nlrp3-/- mice, endothelium-specific Nlrp3 knockout mice (EC-Nlrp3-/-) and their wild type littermates. We will then investigate the non-inflammatory effects of TMAO leading to endothelium dependent vasodilation, pyroptosis and DAMPs production both in vitro and in vivo. Lastly, we will explore the novel molecular signaling pathways mediating TMAO-induced endothelial exosome release leading to endothelial dysfunction and vascular injury. The proposed studies will reveal new mechanistic insights of CVD pathogenesis induced by microbial metabolites such as TMAO and will pave way to the development of clinically relevant, novel therapeutic strategies for treating atherosclerosis and resulting CVDs.

项目摘要心血管疾病（CVD）与发达国家的50％有关，因此是一个主要健康问题，我们仍然远离治愈。除了CVD的传统风险因素外，肠道微生物代谢物对CVD发病机理施加的影响仅在最近。三甲胺-N-氧化物（TMAO），一种肠道微生物衍生的饮食代谢物在CVD患者的循环中，磷脂酰胆碱/肉碱升高，与啮齿动物和人类的动脉粥样硬化和CVD进展。目前的赠款提案试图定义新型分子信号传导机制介导动脉内皮细胞（EC）对TMAO的反应，这将为内皮功能障碍和相关血管损伤的发病机理提供新的见解动脉粥样硬化。我们的初步结果表明，tmao诱导的NLRP3炎性症具有直接对内皮细胞的作用。因此，tmao引起炎症和非炎症效应内皮功能障碍和最终动脉粥样硬化。这些代表了新型的致病机制 tmao超越炎症。基于这些观察结果，我们假设肠道微生物代谢物此类作为内源性危险信号的循环作用的tmao，并诱导两者炎症和非炎症反应导致内皮功能障碍和血管损伤，这，这些反应因此，在动脉壁中表现为动脉粥样硬化。为了检验这一假设，我们将解决如何 TMAO使用NLRP3 - / - 小鼠，内皮特异性诱导体内内皮功能障碍和动脉粥样硬化 NLRP3基因敲除小鼠（EC-NLRP3 - / - ）及其野生式同窝仔。然后，我们将研究非炎症 TMAO导致内皮依赖性血管舒张，凋亡和潮湿产生的影响既体内和体内。最后，我们将探索介导TMAO诱导的新型分子信号通路内皮外泌体释放导致内皮功能障碍和血管损伤。拟议的研究将揭示了由微生物代谢物（如TMAO）诱导的CVD发病机理的新机械见解，例如为开发临床相关的新型治疗策略的铺平方法，以治疗动脉粥样硬化和由此产生的CVD。