Novel Role of Lactate for Cardiovascular Dysfunction in Sepsis

乳酸对脓毒症心血管功能障碍的新作用

• 批准号: 10397654
• 负责人: Chuanfu Li
• 金额: $ 54.86万
• 依托单位: EAST TENNESSEE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10397654
• 关键词: Acute; Acute Respiratory Distress Syndrome; Biological Markers; Cadherins; Cardiomyopathies; Cardiovascular Physiology; Cardiovascular system; Cell membrane; Cell physiology; Cellular Membrane; Cessation of life; Clathrin; Clinical; Clinical Data; Complex; Complication; Critical Illness; Critical Pathways; Data; Development; Disease; Endocytosis; Endosomes; Endothelial Cells; Endothelium; Enzymes; Event; Functional disorder; Glycolysis; Goals; Guidelines; Immune System Diseases; Immune response; Infection; Inflammatory Response; Innovative Therapy; Knowledge; LATS1 gene; Life; Liquid substance; Lysosomes; Mediating; Metabolism; Molecular; Morbidity - disease rate; Multiple Organ Failure; Myocardium; Organ; Patients; Permeability; Phosphorylation; Play; Production; Proteins; Resuscitation; Role; Sepsis; Sepsis Syndrome; Septic Shock; Serum; Severities; Signal Pathway; Signal Transduction; Systemic Inflammatory Response Syndrome; Therapeutic; Tight Junctions; Trauma; United States; Vascular Diseases; Vascular Endothelium; Vascular Permeabilities; angiogenesis; base; cadherin 5; caveolin 1; cecal ligation puncture; effective therapy; heart function; hexokinase; improved; inhibitor; mortality; mouse model; novel; novel therapeutic intervention; novel therapeutics; organ injury; polymicrobial sepsis; prevent; receptor; septic; survival outcome

Cardiovascular dysfunction is a major complication associated with sepsis induced morbidity and mortality. Sepsis is life-threatening organ dysfunction caused by a dysregulated host response to infection4. The recent Sepsis-3 guidelines recommend that persistence of serum lactate >2 mmol/L, despite adequate fluid resuscitation, should be included as a new criteria when clinically defining septic shock. Clinical data shows that lactate levels correlate strongly and positively with severity, morbidity and mortality in sepsis. Although lactate is a well-accepted biomarker of sepsis, recent evidence indicates that lactate may play a pathophysiological role in sepsis induced cardiovascular dysfunction. We have made a novel discovery that high levels of lactate directly cause vascular dysfunction and cardiomyopathy in polymicrobial sepsis. Specifically, we discovered that elevated serum lactate levels in a mouse model of cecal ligation and puncture (CLP) sepsis significantly increased vascular permeability, worsened cardiomyopathy, and accelerated mortality. In contrast, inhibition of lactate production by suppression of hexokinase in glycolysis, significantly improved survival outcome and cardiac function in CLP sepsis. Importantly, our preliminary data shows that lactate significantly decreased cadherins junction protein (vascular endothelial cadherine, VE-cadherine) and tight junction protein-1 ZO-1 in the myocardium. VE- cadherin and ZO1 are important proteins for endothelial cell barrier function. We also found that lactate markedly stimulated yes associated protein (YAP) phosphorylation and induced YAP disassociated with VE- cadherin, resulting in VE-cadherin translocation from cell membrane into endosome/lysosome for degradation. Our findings suggest that high levels of lactate exerts deleterious effects on cardiovascular function during sepsis. The goals of this application are to decipher the cellular and molecular mechanisms of lactate mediated cardiovascular dysfunction during polymicrobial sepsis. Based on our novel findings, we hypothesize that “lactate is a novel endogenous effector which mediates cardiovascular dysfunction in sepsis by disassociation of VE-cadherin with YAP and promoting VE-cadherin translocation to endosomes/lysosomes, resulting in endothelial barrier dysfunction”. Specific aim 1. Investigate whether lactate mediates endothelial cell permeability via disassociation of YAP with VE-cadherin on cell membrane. In this aim, we will investigate whether lactate decreased YAP levels are mediated through activation of AMPK and LATS1/2 signaling. We will also investigate whether YAP plays an important role in the stabilization of VE-cadherin on cellular membrane in endothelial cells and regulates the expression of VE-cadherin and tight junction proteins. Specific aim 2. Define the role of lactate receptor, GPR81 in lactate induced vascular permeability during sepsis. In this aim, we will investigate whether lactate promoted VE-cadherin translocation to endosomes/lysosomes is mediated by its receptor, GPR81 mediated mechanisms. We will investigate the role of GPR81 mediated Akt/ERK signaling in lactate induced endothelial cell barrier dysfunction during sepsis. Specific aim 3. Determine whether suppressing lactate production and/or blocking the lactate receptor, GPR81, will have therapeutic potential in sepsis. In this aim, we will evaluate whether suppression of lactate production and simultaneously blockade of the lactate receptor GPR81 will prevent sepsis induced cardiovascular dysfunction and treat septic sequelae. Significance/impact: Successful completion of the proposed studies will result in a wealth of new and novel data on the mechanistic role of lactate in cardiovascular dysfunction during sepsis. These new data will be the basis for the development of innovative therapies for septic cardiovascular dysfunction which will result in improved survival outcome.

心血管功能障碍是败血症引起的发病率和死亡率相关的主要并发症。 败血症是威胁生命的器官功能障碍，这是由于对感染的宿主反应失调引起的4。最近 SEPIS-3指南建议血清渗透的持久性> 2 mmol/L，首选足够的液体 复苏，在临床定义败血性休克时应将其作为新标准。临床数据显示 这使水平与败血症的严重程度，发病率和死亡率密切相关。虽然 鞋底是败血症的一个良好接受的生物标志物，最近的证据表明鞋底可以发挥作用 败血症中的病理生理作用引起的心血管功能障碍。 我们已经做出了一个新颖的发现，即高水平的乳酸直接引起血管功能障碍和 多症状败血症中的心肌病。具体来说，我们发现在 小鼠结扎和穿刺（CLP）败血症的小鼠模型显着增加了血管通透性， 心肌病恶化，死亡率加速。相反，通过 在糖酵解中抑制己糖激酶，CLP中的生存结果和心脏功能显着改善 败血症。重要的是，我们的初步数据表明，裂缝可显着改善钙粘蛋白的连接蛋白 （血管内皮核蛋白，VE-钙胺）和心肌中的紧密连接蛋白-1 ZO-1。 ve 钙粘蛋白和ZO1是内皮细胞屏障功能的重要蛋白质。我们还发现乳酸 明显刺激的是相关蛋白（YAP）磷酸化，并诱导的YAP与VE-相关 钙粘蛋白，导致VE-钙粘蛋白从细胞膜转运为内体/溶酶体 降解。我们的发现表明，高水平的鞋底对心血管执行有害影响 败血症期间的功能。 该应用的目标是破译鞋底介导的细胞和分子机制 多因素败血症期间的心血管功能障碍。根据我们的新发现，我们假设 “鞋底是一种新型的内源性效应子，可通过 VE-钙粘着蛋白与YAP的分离，并促进VE-钙粘蛋白转运至内体/溶酶体， 导致内皮屏障功能障碍。 特定目的1。调查缝隙是否通过 YAP与细胞膜上的VE-钙粘着蛋白分解。在此目标中，我们将调查是否 通过激活AMPK和LATS1/2信号传导介导的YAP降低水平介导。我们也会 研究YAP在VE-钙粘蛋白在细胞膜上的稳定中是否起重要作用 内皮细胞并调节VE-钙粘蛋白和紧密连接蛋白的表达。 具体目标2。定义乳酸受体，GPR81在乳酸诱导的血管通透性中的作用 在败血症期间。在此目的中，我们将调查是否促进了辅助辅助蛋白转运到 内体/溶酶体由其接收器GPR81介导的机制介导。我们将调查 GPR81介导的AKT/ERK信号在鞋底诱导的内皮细胞屏障功能障碍中的作用 败血症。 特定目标3。确定是否抑制乳酸产生和/或阻塞乳酸 受体GPR81在败血症中具有治疗潜力。在此目标中，我们将评估是否 抑制乳酸产生和简单地阻断乳酸受体GPR81将阻止 败血症诱导心血管功能障碍并治疗化粪池后遗症。 意义/影响：成功完成拟议的研究将导致大量新的和 败血症期间鞋底在心血管功能障碍中的机理作用的新数据。这些新数据将 成为开发脓毒症心血管功能障碍创新疗法的基础，该疗法将 导致生存结果改善。