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: 10609873
• 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 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10609873
• 关键词: Acceleration; 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; Recommendation; Resuscitation; Role; Sepsis; Sepsis Syndrome; Septic Shock; Serum; Severities; Signal Pathway; Signal Transduction; Syndrome; Systemic Inflammatory Response Syndrome; Therapeutic; Tight Junctions; Trauma; United States; Vascular Diseases; Vascular Endothelium; Vascular Permeabilities; angiogenesis; cadherin 5; caveolin 1; cecal ligation puncture; effective therapy; heart function; hexokinase; improved; inhibitor; mortality; mouse model; novel; novel therapeutic intervention; 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.

心血管功能障碍是脓毒症引起的发病率和死亡率的主要并发症。 脓毒症是一种威胁生命的器官功能障碍，由宿主对感染的反应失调引起。最近的 脓毒症-3指南建议，尽管有足够的液体，血清乳酸水平仍应保持在2 mmoL/L 在临床定义感染性休克时，应将复苏作为一项新的标准。临床数据显示 败血症的严重程度、发病率和死亡率与乳酸水平密切相关。虽然 乳酸是公认的败血症的生物标志物，最近的证据表明乳酸可能在 脓毒症所致心血管功能障碍的病理生理学作用。 我们有了一个新的发现，高水平的乳酸直接导致血管功能障碍和 多菌败血症中的心肌病。具体地说，我们发现，升高的血清乳酸水平 盲肠结扎穿孔(CLP)小鼠脓毒症模型显著增加血管通透性， 加重了心肌病，加速了死亡率。相比之下，通过抑制乳酸的产生 抑制糖酵解中的己糖激酶，显著改善CLP的生存结局和心功能 败血症。重要的是，我们的初步数据显示，乳酸显著降低了钙粘素连接蛋白。 (血管内皮钙粘素，VE-钙粘素)和紧密连接蛋白-1 ZO-1在心肌中的表达。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 显著刺激YAP的磷酸化，并诱导YAP与VE去依赖- 钙粘附素，导致VE-钙粘附素从细胞膜转位到内体/溶酶体 退化。我们的发现表明，高水平的乳酸对心血管有有害影响 在脓毒症期间发挥作用。 这项应用的目标是破译乳酸介导的细胞和分子机制。 多菌败血症时的心血管功能障碍。根据我们的新发现，我们假设 乳酸是一种新的内源性效应物，通过以下途径介导脓毒症患者的心血管功能障碍 VE-钙粘附素与YAP解离并促进VE-钙粘附素转位到内体/溶酶体， 导致内皮屏障功能障碍“。 具体目的1.研究乳酸是否通过 YAP与VE-钙粘附素在细胞膜上的解离。为此，我们将调查是否 乳酸降低YAP水平是通过激活AMPK和LATS1/2信号途径实现的。我们还将 探讨YAP在VE-钙粘附素稳定细胞膜中的作用 并调节VE-钙粘蛋白和紧密连接蛋白的表达。 特定目的2.明确乳酸受体GPR81在乳酸诱导的血管通透性中的作用 在脓毒症期间。为此，我们将研究乳酸是否促进VE-钙粘附素易位到 内质体/溶酶体是由其受体GPR81介导的。我们将调查 GPR81介导的Akt/ERK信号在乳酸诱导的内皮细胞屏障功能障碍中的作用 败血症。 具体目标3.确定是否抑制乳酸的产生和/或阻断乳酸 受体GPR81将在脓毒症中具有治疗潜力。在这个目标中，我们将评估是否 抑制乳酸的产生，同时阻断乳酸受体GPR81将防止 脓毒症引起心血管功能障碍，治疗败血症后遗症。 意义/影响：成功完成拟议的研究将产生大量新的和 败血症期间乳酸在心血管功能障碍中的机制作用的新数据。这些新数据将 为开发感染性心血管功能障碍的创新疗法奠定基础 结果改善了生存结果。

项目成果

LACTATE IMPAIRS VASCULAR PERMEABILITY BY INHIBITING HSPA12B EXPRESSION VIA GPR81-DEPENDENT SIGNALING IN SEPSIS.

• DOI: 10.1097/shk.0000000000001983
• 发表时间: 2022-10-01
• 期刊: Shock (Augusta, Ga.)

Cardiovascular Dysfunction in COVID-19: Association Between Endothelial Cell Injury and Lactate.

• DOI: 10.3389/fimmu.2022.868679
• 发表时间: 2022
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Yang K;Holt M;Fan M;Lam V;Yang Y;Ha T;Williams DL;Li C;Wang X
• 通讯作者: Wang X

Lactate promotes macrophage HMGB1 lactylation, acetylation, and exosomal release in polymicrobial sepsis.

乳酸促进巨噬细胞HMGB1乳糖，乙酰化和外座子体释放中的多因素败血症。

• DOI: 10.1038/s41418-021-00841-9
• 发表时间: 2022-01
• 期刊: Cell death and differentiation
• 影响因子: 12.4
• 作者: Yang K;Fan M;Wang X;Xu J;Wang Y;Tu F;Gill PS;Ha T;Liu L;Williams DL;Li C
• 通讯作者: Li C

Lactate induces vascular permeability via disruption of VE-cadherin in endothelial cells during sepsis.

• DOI: 10.1126/sciadv.abm8965
• 发表时间: 2022-04-29
• 期刊: SCIENCE ADVANCES
• 影响因子: 13.6
• 作者: Yang, Kun;Fan, Min;Wang, Xiaohui;Xu, Jingjing;Wang, Yana;Gill, P. Spencer;Ha, Tuanzhu;Liu, Li;Hall, Jennifer, V;Williams, David L.;Li, Chuanfu
• 通讯作者: Li, Chuanfu

Lactate promotes endothelial-to-mesenchymal transition via Snail1 lactylation after myocardial infarction.

乳酸在心肌梗塞后通过Snail1乳糖促进内皮到间质转变。

• DOI: 10.1126/sciadv.adc9465
• 发表时间: 2023-02-03
• 期刊: Science advances
• 影响因子: 13.6