Role of Trimethylamine-N-oxide in endothelial dysfunction

项目摘要 在发达国家，心血管疾病(CVD)与50%的死亡有关，因此是主要的 健康问题，我们仍然离治愈还很远。除了心血管疾病的传统风险因素外， 肠道微生物代谢产物对心血管疾病发病机制的影响仅在 最近几次。三甲胺-N-氧化物(TMAO)，一种肠道微生物衍生的膳食代谢物 CVD患者循环中的磷脂酰胆碱/肉碱升高，并与 啮齿动物和人类的动脉粥样硬化和心血管疾病进展。本赠款提案试图界定 介导动脉内皮细胞对TMAO反应的新的分子信号机制 这将为内皮功能障碍和相关的血管损伤的发病机制提供新的见解。 动脉粥样硬化。我们的初步结果表明，TMAO诱导的Nlrp3炎性小体具有直接的 对血管内皮细胞的作用。因此，TMAO既有炎症作用，又有非炎症作用 导致内皮功能障碍，最终导致动脉粥样硬化。这些代表了新的致病机制。 TMAO超越炎症。基于这些观察，我们假设肠道微生物代谢产物 由于TMAO被释放到循环中，作为内源性危险信号，并导致 炎性和非炎性反应导致内皮功能障碍和血管损伤 从而表现为动脉壁的动脉粥样硬化。为了检验这一假设，我们将解决如何 内皮特异的Nlrp3-/-小鼠体内TMAO诱导的内皮功能障碍和动脉粥样硬化 NLRP3基因敲除小鼠(EC-Nlrp3-/-)及其野生型窝仔。然后我们将调查非炎症性 TMAO对大鼠内皮依赖性血管扩张、下睑下垂和血管内皮细胞产生抑制物的影响 体外和体内。最后，我们将探索介导TMAO诱导的新的分子信号通路 内皮外切体的释放会导致内皮功能障碍和血管损伤。拟议的研究将 揭示TMAO和Will等微生物代谢产物诱导CVD发病的新机制 为开发临床相关的治疗动脉粥样硬化的新治疗策略铺平道路 由此产生的心血管疾病。

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.