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
基本信息
- 批准号:10192825
- 负责人:
- 金额:$ 54.86万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AcuteAdult Respiratory Distress SyndromeBiological MarkersCadherinsCardiomyopathiesCardiovascular PhysiologyCardiovascular systemCell membraneCell physiologyCellular MembraneCessation of lifeClathrinClinicalClinical DataComplexComplicationCritical IllnessCritical PathwaysDataDevelopmentDiseaseEndocytosisEndosomesEndothelial CellsEndotheliumEnzymesEventFunctional disorderGlycolysisGoalsGuidelinesImmune System DiseasesImmune responseInfectionInflammatory ResponseInnovative TherapyKnowledgeLATS1 geneLifeLiquid substanceLysosomesMediatingMetabolismMolecularMorbidity - disease rateMultiple Organ FailureMyocardiumOrganPatientsPermeabilityPhosphorylationPlayProductionProteinsResuscitationRoleSepsisSepsis SyndromeSeptic ShockSerumSeveritiesSignal PathwaySignal TransductionSystemic Inflammatory Response SyndromeTherapeuticTight JunctionsTraumaUnited StatesVascular DiseasesVascular EndotheliumVascular Permeabilitiesangiogenesisbasecadherin 5caveolin 1cecal ligation punctureeffective therapyheart functionhexokinaseimprovedinhibitor/antagonistmortalitymouse modelnovelnovel therapeutic interventionnovel therapeuticsorgan injurypolymicrobial sepsispreventreceptorsepticsurvival outcome
项目摘要
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.
心血管功能障碍是与败血症引起的发病率和死亡率相关的主要并发症。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Chuanfu Li其他文献
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{{ truncateString('Chuanfu Li', 18)}}的其他基金
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 - 财政年份:2020
- 资助金额:
$ 54.86万 - 项目类别:
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 - 财政年份:2020
- 资助金额:
$ 54.86万 - 项目类别:
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:
10027071 - 财政年份:2020
- 资助金额:
$ 54.86万 - 项目类别:
Innate immunity and cardiovascular function in sepsis
脓毒症的先天免疫和心血管功能
- 批准号:
8307963 - 财政年份:2009
- 资助金额:
$ 54.86万 - 项目类别:
Innate immunity and cardiovascular function in sepsis
脓毒症的先天免疫和心血管功能
- 批准号:
7901577 - 财政年份:2009
- 资助金额:
$ 54.86万 - 项目类别:
Innate Immunity and Cardiovascular Function in Sepsis
脓毒症的先天免疫和心血管功能
- 批准号:
9767811 - 财政年份:2009
- 资助金额:
$ 54.86万 - 项目类别:
Innate immunity and cardiovascular function in sepsis
脓毒症的先天免疫和心血管功能
- 批准号:
8118998 - 财政年份:2009
- 资助金额:
$ 54.86万 - 项目类别:
Equipment Supplement request for an Octet RED96 biolayer interferometry instrument
Octet RED96 生物层干涉测量仪器的设备补充请求
- 批准号:
9027318 - 财政年份:2009
- 资助金额:
$ 54.86万 - 项目类别:
Innate Immunity and Cardiovascular Function in Sepsis
脓毒症的先天免疫和心血管功能
- 批准号:
9927632 - 财政年份:2009
- 资助金额:
$ 54.86万 - 项目类别:
Innate Immunity and Cardiovascular Function in Sepsis
脓毒症的先天免疫和心血管功能
- 批准号:
8792849 - 财政年份:2009
- 资助金额:
$ 54.86万 - 项目类别:
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