Dual Functionality of Ceramide in Human Microvascular Endothelial Function

神经酰胺在人体微血管内皮功能中的双重功能

• 批准号: 10636908
• 负责人: Julie K Freed
• 金额: $ 63.24万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10636908
• 关键词: Address; Adipose tissue; Antiinflammatory Effect; Arteries; Atherosclerosis; Blood Vessels; Cardiac; Cardiovascular Diseases; Ceramides; Chronic; Complement; Coronary; Coronary Arteriosclerosis; Data; Development; Dilator; Disease; EFRAC; Endothelium; Event; Exposure to; Fatty acid glycerol esters; Generations; Goals; Health; Heart failure; Human; Hydrogen Peroxide; Individual; Knowledge; Mediating; Mediator; Metabolism; Microcirculation; Microvascular Dysfunction; Mitochondria; NADPH Oxidase; NOS3 gene; Nitric Oxide; Pathogenicity; Pathologic; Pathway interactions; Patients; Perfusion; Peripheral; Phenotype; Plasma; Play; Production; Research; Risk; Risk Factors; Role; Signal Transduction; Sphingolipids; Sphingosine-1-Phosphate Receptor; Stress; Therapeutic Intervention; Tissues; Vascular Endothelium; acute stress; arteriole; caveolin 1; endothelial dysfunction; in vivo; inflammatory milieu; new therapeutic target; novel; novel strategies; preservation; pressure; prevent; response; shear stress; sphingosine 1-phosphate; targeted treatment; theories; translational approach; translational study; vascular endothelial dysfunction; volunteer

Project Summary Elevated levels of plasma ceramide are an independent risk factor for major adverse cardiac events (MACE) and are associated with cardiovascular diseases including coronary artery disease (CAD) and heart failure with preserved ejection fraction (HFpEF). Endothelial microvascular dysfunction, the loss of nitric oxide (NO)- mediated dilation to flow (flow-induced dilation; FID), precedes the development of CAD and occurs following chronic exposure to exogenous ceramide. During disease, following acute stress (e.g. high pressure), or after chronic ceramide treatment, FID is maintained by utilizing mitochondrial-derived hydrogen peroxide (H2O2). Although effective at eliciting dilation, unlike the anti-inflammatory effects of NO, H2O2 promotes an inflammatory environment within the vasculature and surrounding parenchymal tissue. The mechanism(s) by which ceramide promotes mitochondrial H2O2-mediated FID remains unknown. Interestingly, ceramide has also been implicated as a critical signaling component in the generation of NO. The ceramide metabolite sphingosine-1-phosphate (S1P) exerts opposing effects on the endothelium, promotes the formation of NO, and may explain the positive vascular effects associated with ceramide. A large knowledge gap exists regarding the dual functionality of ceramide within the human microvascular endothelium. We hypothesize that while ceramide formation is a critical mechanistic component in NO-mediated FID, prolonged exposure initiates a signaling cascade that results in the release of mitochondrial H2O2 in response to shear. Our aims are as follows; 1) determine the necessary role of ceramide in maintaining NO-mediated FID within the human microcirculation, and 2) investigate the mechanism(s) by which ceramide formation during stress or disease initiates the transition in FID mediator from NO to mitochondrial-derived H2O2. Using a novel approach, these mechanistic studies will be complemented by the first human in vivo study to examine the effect of elevated plasma ceramide on peripheral microvascular function. The translational studies proposed in this application will enhance our understanding of ceramide signaling during health, disease, and following acute stress. This information will provide new targets for therapeutic intervention in individuals at risk for developing cardiovascular disease including CAD and HFpEF.

项目概要 血浆神经酰胺水平升高是主要不良心脏事件 (MACE) 的独立危险因素 与心血管疾病有关，包括冠状动脉疾病（CAD）和心力衰竭 保留射血分数（HFpEF）。内皮微血管功能障碍、一氧化氮 (NO) 损失 - 介导的扩张至血流（血流诱导扩张；FID），先于 CAD 发生，并发生在 CAD 之后 长期接触外源性神经酰胺。疾病期间、急性应激（例如高压）之后或之后 慢性神经酰胺治疗中，FID 通过利用线粒体衍生的过氧化氢 (H2O2) 来维持。 虽然 H2O2 可有效引起扩张，但与 NO 的抗炎作用不同，H2O2 会促进炎症 脉管系统和周围实质组织内的环境。神经酰胺的作用机制 促进线粒体 H2O2 介导的 FID 仍然未知。有趣的是，神经酰胺也与此有关 作为 NO 生成过程中的关键信号成分。神经酰胺代谢物 1-磷酸鞘氨醇 (S1P) 对内皮发挥相反作用，促进 NO 的形成，并可能解释积极的作用 与神经酰胺相关的血管效应。关于双重功能存在很大的知识差距 人体微血管内皮内的神经酰胺。我们假设虽然神经酰胺的形成是 作为 NO 介导的 FID 的关键机制组成部分，长时间暴露会引发信号级联反应， 导致线粒体响应剪切力释放 H2O2。我们的目标如下： 1）确定 神经酰胺在维持人体微循环内 NO 介导的 FID 方面的必要作用，以及 2) 研究应激或疾病期间神经酰胺形成引发 FID 转变的机制 从 NO 到线粒体衍生的 H2O2 的介质。使用新颖的方法，这些机制研究将 并辅之以第一项人体体内研究，以检查升高的血浆神经酰胺对外周血管的影响 微血管功能。本申请中提出的转化研究将增强我们对 健康、疾病和急性应激后的神经酰胺信号传导。这些信息将提供新的目标 对有心血管疾病风险的个体进行治疗干预，包括 CAD 和 HFpEF。