Sub-cellular Targeting of Endothelial ROS in Myocardial Ischemia
Sub-cellular Targeting of Endothelial ROS in Myocardial Ischemia
批准号:
10705336
负责人:
Ruhul Abid
金额:
$61.32万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2017
资助国家:
美国
项目状态:
已结题
起止时间:
2017-08-10 至 2024-08-31
关键词:
3-nitrotyrosineAMP-activated protein kinase kinaseAddressAnabolismAnimal ModelAnimalsAntioxidantsArteriesBiogenesisBiological AssayBlood VesselsBrain Hypoxia-IschemiaCardiac Surgery proceduresCardiovascular DiseasesCell ProliferationCell SurvivalChronicCoagulation ProcessComplexCongressesCoronaryCoronary ArteriosclerosisCoronary VesselsDataDown-RegulationElectron TransportElectronsEndothelial CellsEndotheliumEnergy SupplyExposure toExtravasationFamily suidaeFibrinFundingGenerationsGlucoseGlycolysisGrantHeartHeart AtriumHumanHypoxiaIncubatedInfarctionIschemiaLateralLigationManuscriptsMeasuresMediatingMembrane PotentialsMitochondriaModelingMolecularMorbidity - disease rateMusMyocardial InfarctionMyocardial IschemiaNADPH OxidaseNutrientOperative Surgical ProceduresOutcomeOxidantsOxidative PhosphorylationOxidative StressOxygenOxygen ConsumptionPatientsProductionProteomicsPublishingReactive Oxygen SpeciesRecoveryRecovery of FunctionReportingResearchSOD2 geneSourceStrokeSystemTherapeuticTissuesTransgenesTransgenic AnimalsTransgenic OrganismsUnited States National Institutes of HealthVascular EndotheliumWorkameroidangiogenesisbasecardiac angiogenesiscardiovascular disorder preventiondensityextracellularfatty acid oxidationgenetic manipulationheart functionimprovedin vivoin vivo evaluationinnovationinsightmimeticsmitochondrial membranenanodrugnanoparticlenanoparticle drugneoplastic cellnormoxianovelnovel strategiesoverexpressionphosphoproteomicspreservationpreventrecruitresiliencesubcellular targetingtrend
中文摘要
续订申请是基于新的发现,即减少有丝分裂-ROS,使用基因
操纵和/或纳米药物,改善冠状动脉内皮细胞的存活和增殖并帮助恢复
心肌梗死(MI)后动物模型和人类心房组织的心功能。初步调查结果
在目前的应用中证明了使用转基因(MnSOD)和纳米药物减少有丝分裂-ROS
(JP4-039,XJB5-131)诱导线粒体复合体I的生物发生(蛋白质组和磷蛋白质组数据)
内皮细胞氧化磷酸化(Ox-PHOS)导致冠脉血管生成和心功能恢复
在心肌梗死后的心脏。
这是一项创新
EC像大多数肿瘤细胞一样,利用厌氧糖酵解作为ATP的主要来源(85%)
因此,从较少的转变-
高效的能量产生系统糖酵解(2个ATP/葡萄糖分子),转化为更有效的Ox-Phos(34-36
ATP/葡萄糖)可能为缺血(低糖、低氧)所需的内皮细胞提供关键的能量支持。这里,
我们建议检验一个新的总体假设,即MITO-ROS的调制可以改善
而EC线粒体主要参与dNTP的生物合成。
Δψm和
形成高效的电子传输链(ETC)的超络合物(SC)和Ox-Phos介导的
缺血时内皮细胞产生三磷酸腺苷。这一转变从
糖酵解为更有效的线粒体Ox-PHOS
在心肌缺血的“能量危机”期间,可能为冠脉内皮细胞提供韧性/存活率。
治疗性
干预亚细胞内ROS水平的好处将通过对MITO-ROS的特异性下调来实现
在已经暴露于缺血/缺氧的内皮细胞中。这一假设将在体内得到充分验证,使用我们的
新型EC特异性转基因MnSOD动物及其支持应用
线粒体特异性氮氧化物和纳米抗氧化剂在大动物模型(猪)和冠状动脉中的作用
接受心脏手术的心血管疾病患者的血管。我们提出了三个具体目标。目标1:澄清
线粒体ROS调节保护冠状动脉内皮细胞免受氧化损伤的分子机制
在心肌缺血期间应激并诱导冠脉血管生成。利用超氧化物歧化酶-维生素E转基因动物
和模拟心肌梗死(LAD结扎)手术,Δψm,超复合体(SC)形成,氧气
消耗率(OCR)与胞外酸化率(ECAR),即ATP合成,将进行评估。目标
2:确定线粒体靶向MnSOD模拟物(JP4-039,XJB-5-131)纳米粒对
小鼠心肌梗死后血管密度与心功能恢复及慢性心肌缺血
大型动物(猪)。目的3:阐明线粒体抗氧化剂的分子机制
纳米粒(JP4-039/XJB-5-131)提高人冠状动脉血管新生能力
手术患者)体外。这项研究使用了独特的动物模型、人类心房组织和线粒体-
特定的抗氧化剂将为MITO-ROS改善EC的机制提供新的见解
通过招募线粒体作为缺血期间的有效能量生成器来存活和血管生成。
英文摘要
renewal application is based on the novel findings that reduction in mito-ROS, using genetic
manipulation and/or nanoparticle drugs, improve survival and proliferation of coronary EC and help recover
cardiac function in a post-myocardial infarct (MI) animal model and human atrial tissue. Preliminary findings
in the current application demonstrate that reduction of mito-ROS using transgene (MnSOD) and nanodrugs
(JP4-039, XJB5-131) induce mitochondrial complex I biogenesis (proteomic and phosphoproteomic data)
and oxidative phosphorylation (Ox-Phos) in EC resulting in coronary angiogenesis cardiac function recovery
in post-MI heart.
This innovative
EC, like most tumor cells, utilizes anerobic glycolysis as a major (85%) source of ATP
Thus, the shift from less-
efficient energy production system glycolysis (2 ATP/glucose molecule), to a more efficient Ox-Phos (34-36
ATP/glucose) may provide critical energy support to EC needed during ischemia (low glucose, oxygen). Here,
we propose to examine a novel overarching hypothesis that modulation of mito-ROS improves
production, while EC mitochondria are mostly involved in dNTP biosynthesis.
Δψm and
‘super-complex’ (SC) formation resulting in efficient electron transport chain (ETC) and Ox-Phos-mediated
ATP generation in EC during ischemia. This shift from
glycolysis to a more efficient mitochondrial Ox-Phos
may provide resilience/survival to coronary EC during ‘energy crisis’ in myocardial ischemia.
The therapeutic
benefit of intervening on subcellular ROS level will be best realized by specific down regulation of mito-ROS
in ECs that have been exposed to ischemia/hypoxia. This hypothesis will be fully tested in vivo using our
novel EC-specific transgenic MnSOD (SOD-OE; mitochondrial antioxidant) animals and supported using
mitochondria-specific nitroxide and nanoparticle antioxidant in large animal model (swine) and in coronary
vessels from CVD patients undergoing cardiac surgery. We propose three Specific Aims. Aim 1: Elucidate
the molecular mechanisms by which modulation of mitochondrial ROS protect coronary EC from oxidative
stress and induce coronary angiogenesis during myocardial ischemia. Using SOD-VE transgenic animals
and myocardial infarct-mimicking (LAD ligation) surgeries, Δψm, super-complex (SC) formation, oxygen
consumption rate (OCR) versus extracellular acidification rate (ECAR), ATP synthesis, will be assessed. Aim
2: Determine the effects mitochondria-targeted MnSOD-mimetic (JP4-039, XJB-5-131) nanoparticles on
post-infarct vessel density and recovery of cardiac function in mice and on chronic myocardial ischemia in
large animals (swine). Aim 3: Elucidate the molecular mechanisms by which mitochondrial antioxidant
nanoparticles (JP4-039/XJB-5-131) improve angiogenic potential of human coronary vessels (from cardiac
surgery patients) ex vivo. This study using unique animal models, human atrial tissue, and mitochondria-
specific antioxidant will provide novel insights into the mechanisms by which mito-ROS can improve EC
survival and angiogenesis by recruiting mitochondria as an efficient energy generator during ischemia.
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会议论文
Sub-cellular Targeting of Endothelial ROS in Myocardial Ischemia
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