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Implications of Endothelial-Myocyte Uncoupling in Cardiac Arrhythmia

Implications of Endothelial-Myocyte Uncoupling in Cardiac Arrhythmia
内皮-肌细胞解偶联对心律失常的影响
批准号:
7408062
负责人:
Suresh C. Tyagi
金额:
$37.0万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2007
资助国家:
美国
项目状态:
已结题
起止时间:
2007-04-18 至 2011-03-31
关键词:
3-deazaadenosineAbbreviationsAcetylcholineAddressAdenosine DiphosphateAgonistAlteplaseAortaArginineArrhythmiaAttenuatedBasement membraneBradykininBreedingCardiacChronicCollagenConnexin 43CouplingCrossbreedingCystathionineDisintegrinsDisruptionDoseEKG QRS ComplexEchocardiographyEicosatrienoic AcidElastinElectrocardiogramEndothelial CellsEndothelin-1EndotheliumEnvironmentExtracellular MatrixFailureFibrosisFistulaFluorescent DyesGelatinase AGoalsHeartHeart RateHeart failureHeterozygoteHomocysteineHomocystineHomozygoteHydrolaseHydroxyeicosatetraenoic AcidsHyperhomocysteinemiaImageIn SituKnock-outLabelLeft ventricular structureLipopolysaccharidesLocalizedMTHFR geneMatrix MetalloproteinasesMeasuresMediatingMetalloproteasesMethionineMethylenetetrahydrofolate reductase (NADPH)MitochondriaMusMuscle CellsN-Methyl-D-Aspartate ReceptorsN-MethylaspartateNADH oxidaseNADPNOS1 protein, humanNeuronsNeurotransmitter ReceptorNiacinamideNitric OxideNitric Oxide SynthaseNitroprussideNorepinephrineOxidation-ReductionOxidesPatternPolymerase Chain ReactionPreparationProductionProteomicsRadioReactive Nitrogen SpeciesReactive Oxygen SpeciesRelaxationResearch PersonnelShunt DeviceSuperoxide DismutaseSuperoxidesTailTelemetryTherapeuticThioredoxinTimeTissue Inhibitor of MetalloproteinasesVeinsVentricular FibrillationVentricular TachycardiaWestern Blottinganalogdizocilpinehuman NOS3 proteinin vivoinnovationmembrane-type matrix metalloproteinaseperoxiredoxinprogramsrelating to nervous systemrelaxing factorresponsesudden cardiac deathtetrahydrobiopterintissue inhibitor of metalloproteinase 4tumor necrosis factor receptor superfamily, member 10b protein, mouse

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中文摘要
翻译
描述(由申请人提供):高同型半胱氨酸(Hcy)水平升高称为高同型半胱氨酸血症(HHcy)与心律失常和心源性猝死(SCO)相关。它增加了iNOS,激活了基质金属蛋白酶(MMP),破坏了连接蛋白43,增加了胶原蛋白/弹性蛋白的比例。连接蛋白43的破坏和胶原蛋白的积累(纤维化)会中断心脏传导,减弱一氧化氮从内皮细胞到肌细胞(E-M)的运输,导致E-M解耦。该建议的新颖之处在于,Hcy作为n -甲基- d -天冬氨酸(NMDA,一种兴奋性神经递质)受体-1的激动剂,阻断NMDA- r1可减少SCO。该建议的中心假设是Hcy增加iNOS, mtNOS活性,超氧化物水平,金属蛋白酶活性,破坏连接蛋白43,加剧内皮-肌细胞解偶联,并通过激活NMDA-R1诱导心力衰竭。具体目的1:确定Hey是否通过增加iNOS并通过作为NMDA-R1的激动剂使eNOS和nNOS无效而加剧心力衰竭和内皮-肌细胞解耦。将CBS杂合子(-/+)敲除(CBSKO)小鼠与iNOS纯合子(-/-)敲除(iNOSKO)小鼠杂交,产生野生型(WT)、CBSKO、iNOSKO和CBS/iNOS(-/+; -/-)双敲除(doubleKO)。在这些小鼠中,慢性容量超负荷心力衰竭将由主动脉-静脉(AV)瘘引起。NMDA-R1将被二唑西平(MK-801)阻断。内皮-肌细胞耦合将在心脏环中确定。测量NMDA-R1、iNOS、nNOS和eNOS的LV水平。具体目的2:确定Hey是否通过诱导NMDA-R1增加心力衰竭患者的MMP-2, -9, -13, ADAM-12,降低TIMP-4,并降解连接蛋白43。MMP和TIMP活性将分别通过创新的2-酶谱(MMP功能蛋白质组学)和反向酶谱测定。连接蛋白43、胶原蛋白和弹性蛋白的降解将通过Western分析来测量。特异性目的#3:确定Hey是否通过激活NMDA-R1降低心衰患者左室线粒体硫氧还蛋白、过氧化物还蛋白和SOD,并增加NADH氧化酶和mtNOS活性。在心脏中,将对硫氧还蛋白、过氧化物还蛋白、SOD和NADH氧化酶进行原位标记。这些研究将描述心律失常和心力衰竭中hcy依赖性内皮-肌细胞解耦的机制,并将对心源性猝死的治疗产生影响。
英文摘要
DESCRIPTION (provided by applicant): Elevated levels of homocysteine (Hcy) known as hyperhomocysteinemia (HHcy) are associated with cardiac arrhythmia and sudden cardiac death (SCO). Hey increases the iNOS, activates matrix metalloproteinase (MMP), disrupts connexin-43 and increases collagen/elastin ratio. The disruption of connexin-43 and accumulation of collagen (fibrosis) interrupts cardiac conduction and attenuate NO transport from endothelium to myocyte (E-M) causing E-M uncoupling. The novelty of this proposal is that Hcy behaves as an agonist to N-methyl-D-aspartate (NMDA, an excitatory neurotransmitter) receptor-1, and blockade of NMDA-R1 reduces SCO. The central hypothesis of this proposal is that Hcy increases iNOS, mtNOS activities, superoxide levels, metalloproteinase activity, disrupts connexin-43, exacerbates endothelial-myocyte uncoupling, and induces cardiac failure by activating NMDA-R1. Specific Aim #1: To determine whether Hey exacerbates heart failure and endothelial-myocyte uncoupling by increasing iNOS and rendering ineffective eNOS and nNOS by behaving as an agonist to NMDA-R1. CBS heterozygote (-/+) knockout (CBSKO) mice will be crossbred with iNOS homozygote (-/-) knockout (iNOSKO) mice, producing wild type (WT), CBSKO, iNOSKO and CBS/iNOS (-/+; -/-) double knockout (doubleKO). In these mice, chronic volume overload heart failure will be created by aorta-venacava (AV) fistula. NMDA-R1 will be blocked by dizocilpine (MK-801). The endothelial-myocyte coupling will be determined in cardiac rings. LV levels of NMDA-R1, iNOS, nNOS and eNOS will be measured. Specific Aim #2: To determine whether Hey increases MMP-2, -9, -13, ADAM-12, decreases TIMP-4, and degrades connexin-43 in heart failure by inducing NMDA-R1. MMP and TIMP activities will be measured by innovative 2-zymography (MMP functional proteomics) and reverse zymography, respectively. The degradation of connexin-43, collagen and elastin will be measured by Western analysis. Specific Aim #3: To determine whether Hey decreases LV mitochondrial thioredoxin, peroxiredoxin, and SOD, and increases NADH oxidase and mtNOS activity in heart failure by activating NMDA-R1. In hearts, in situ labeling will be performed for thioredoxin, peroxiredoxin, SOD, and NADH oxidase. These studies will delineate the mechanism of Hcy-dependent endothelial-myocyte uncoupling in cardiac arrhythmia and failure, and will have therapeutic ramifications for sudden cardiac death.
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  • 项目类别:
  • 资助金额:
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  • 财政年份:
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  • 项目类别:
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    2018
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  • 依托单位:
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  • 批准号:
    10215605
  • 项目类别:
  • 资助金额:
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  • 财政年份:
    2018
  • 负责人:
    Suresh C. Tyagi
  • 依托单位:
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  • 批准号:
    10438112
  • 项目类别:
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  • 财政年份:
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  • 负责人:
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  • 依托单位:
海外基金