Gut microbial metabolite- Trimethylamine-N-oxide and endothelial inflammasome signaling in cardiovascular injury

肠道微生物代谢物-三甲胺-N-氧化物和心血管损伤中的内皮炎性体信号传导

基本信息

批准号：
10002639
负责人：
Sai Sudha Koka
金额：
$ 38.25万
依托单位：
UNIVERSITY OF HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-15 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10002639
关键词：
Abbreviations Address Adhesions Applications Grants Arterial Fatty Streak Arteries Atherosclerosis Blood Circulation Blood Vessels CASP1 gene Cardiovascular Diseases Carnitine Carotid Arteries Cells Choline Chronic Cleaved cell Diet Disease Disease Progression Endothelial Cells Endothelium Exposure to Fluorescence Resonance Energy Transfer Genes Heart Human Impairment In Vitro Inflammasome Inflammation Inflammatory Inflammatory Response Infusion procedures Injury Interleukin-1 Interleukin-1 beta Interleukin-18 Knockout Mice Knowledge Lead Lecithin Link Mediating Membrane Metabolic Molecular Morbidity - disease rate Mus NADPH Oxidase Nitric Oxide Nucleotides Oxidation-Reduction Oxidative Stress Pathogenesis Pathogenicity Pathway interactions Patients Pattern Proteins Reactive Oxygen Species Reporting Residual state Risk Factors Rodent Rodent Model Role Sclerosis Series Signal Transduction Source Stem cells Superoxides T-Lymphocyte Testing Therapeutic Intervention Tight Junctions Vascular Permeabilities Vasodilation atherogenesis base cardiovascular injury cardiovascular risk factor clinical development clinically relevant endothelial dysfunction gut microbes gut microbiota in vivo innovation insight macrophage microbial monocyte mortality new therapeutic target novel novel therapeutics prevent protein aggregate receptor recruit trimethyloxamine vascular inflammation

项目摘要

Project Summary Recent studies have identified intestinal microbe-derived metabolites such as Trimethylamine-N-oxide (TMAO) as a novel risk factor for cardiovascular diseases (CVDs). 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. In spite of this striking association, the molecular mechanisms of how TMAO induces atherosclerosis and CVD progression are still unclear. In this grant proposal, we attempt to elucidate an early intracellular molecular mechanism, namely, the Nlrp3 inflammasome activation, which may switch on endothelial damage through its inflammatory or non-inflammatory pathway leading to endothelial dysfunction and ultimately atherosclerosis. Interestingly, our preliminary studies demonstrated that TMAO-induces the Nlrp3 inflammasome activation and contributes to the endothelial damage and microvascular injury and have also shown that beyond inflammation, the activated inflammasomes have direct actions on the endothelial cells. This may represent a novel pathogenic mechanism of inflammasome activation 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 via Nlrp3 inflammasome activation leading to endothelial dysfunction and vascular injury which consequently manifests into atherogenesis in the arterial wall. To test this hypothesis, we will first determine whether TMAO-induced Nlrp3 inflammasome activation contributes to tight junction disruption, altered vascular permeability, endothelial dysfunction and atherosclerosis in vivo using Nlrp3-/- mice, endothelium-specific Nlrp3 knockout mice (EC-Nlrp3-/-) and their wild type littermates. We will then study how Nlrp3 inflammasomes are activated in endothelial cells by TMAO with a focus on the roles of NADPH oxidase mediated redox signaling and corresponding mechanisms mediating its actions. Finally we will determine the non-inflammatory and inflammatory effects of TMAO activated Nlrp3 inflammasomes on endothelial dysfunction and atherosclerosis by studying the various products such as IL-1β, IL-18, pyroptosis and DAMPs in primary cultures of CAECs and carotid arteries of Nlrp3-/- and Nlrp3+/+ mice. 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 other cardiovascular disorders.

项目摘要最近的研究已经确定了肠道微生物衍生的代谢产物，例如三甲胺-N-氧化物（TMAO）作为心血管疾病（CVD）的新型危险因素。 tmao，饮食中肠道微生物的代谢物在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。尽管存在罢工关联，但分子 TMAO如何影响动脉粥样硬化和CVD进展的机制尚不清楚。在这笔赠款中提案，我们试图阐明早期的细胞内分子机制，即NLRP3炎症体激活可能会通过其炎症或非炎症途径开启内皮损害导致内皮功能障碍并最终导致动脉粥样硬化。有趣的是，我们的初步研究证明TMAO引起的NLRP3炎性体激活并有助于内皮损伤和微血管损伤，还表明，超出感染，激活了炎症体对内皮细胞有直接的作用。这可能代表一种新颖的致病性炎性体激活的机制超出了感染。基于这些观察，我们假设肠道微生物代谢物（例如TMAO）被释放到循环作用中，作为内源性危险信号并通过NLRP3炎症体激活引起炎症和非炎症反应导致内皮功能障碍和血管损伤，因此在动脉壁。为了检验这一假设，我们将首先确定tmao诱导的NLRP3炎症体是否激活导致紧密连接破坏，血管通透性改变，内皮功能障碍和使用NLRP3 - / - 小鼠，内皮特异性NLRP3敲除小鼠（EC-NLRP3 - / - ）及其它们的动脉粥样硬化。野生式同窝仔。然后，我们将研究如何通过TMAO在内皮细胞中激活NLRP3炎症。侧重于NADPH氧化物介导的氧化还原信号传导和相应的机制的作用调解其行动。最后，我们将确定TMAO的非炎症和炎症作用通过研究各种诸如IL-1β，IL-18，凋亡和潮湿的caecs和颈动脉中的潮湿的产物 NLRP3 - / - 和NLRP3+/+小鼠。拟议的研究将揭示CVD发病机理的新机械见解由微生物代谢产物（例如TMAO）诱导的，并将为临床相关的发展铺平道路治疗动脉粥样硬化和其他心血管疾病的新型热策略。