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Hypertension augmented COVID-19 through renin-induced internalization of platelet-ACE2 / SARS-Cov-2 complexes

Hypertension augmented COVID-19 through renin-induced internalization of platelet-ACE2 / SARS-Cov-2 complexes
高血压通过肾素诱导血小板-ACE2/SARS-Cov-2复合物内化增强了COVID-19
批准号:
10490385
负责人:
Thomas M McIntyre
金额:
$57.23万
依托单位国家:
美国
项目类别:
财政年份:
2021
资助国家:
美国
项目状态:
未结题
起止时间:
2021-09-20 至 2025-08-31
关键词:
2019-nCoVACE2AcuteAffinityAgeAgonistAldosteroneAngiotensinogenAnimalsAutopsyBindingBloodBlood CirculationBlood Coagulation DisordersBlood PlateletsBlood coagulationBlood-Air BarrierCOVID-19COVID-19 pandemicCOVID-19 patientCOVID-19 prognosisCOVID-19 riskCardiovascular systemCellsClosure by clampCoagulation ProcessComplexConsumptionDenervationDepositionDiseaseEatingEndothelial CellsEndotheliumEssential HypertensionF2R geneFDA approvedFactor XaFibrinFibrinolytic AgentsFibrosisFunctional disorderGeneticGerman populationHeart InjuriesHumanHypertensionInactive ReninIncidenceInfectionInflammationKidneyLentivirusLiverLungLung diseasesMass Spectrum AnalysisMeasuresMediatingMegakaryocytesMembraneMusNervous System TraumaOrganOutcomePathway interactionsPatientsPatternPepstatinsPeptide HydrolasesPharmaceutical PreparationsPhosphatidylserinesPlasmaPlatelet ActivationPlatelet aggregationProteinsProteolysisPulmonary alveolar structureRNARattusReninReporterReticuloendothelial SystemRiskRisk FactorsRoleRouteSARS-CoV-2 infectionSARS-CoV-2 spike proteinSevere Acute Respiratory SyndromeSignal TransductionSiteSpleenSurfaceSystemTMPRSS2 geneTestingTherapeuticThrombinThrombin ReceptorThrombocytopeniaThromboembolismThromboplastinThrombosisThrombusTissuesTransgenic AnimalsTransgenic OrganismsTropismViralVirusaliskirencell injurycomorbidityfactor IXa-factor VIIIaheart damagehypertensivein vivoinhibitorinnovationliver injurylung injurymacrophagemultiorgan damagenovelnovel strategiesparticleprophylacticprorenin receptorprotein complexreceptorrenal damagerespiratorythromboticthrombotic complicationsuptakevector

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中文摘要
翻译
高血压(原因不明)是COVID-19不良结局的主要共病风险因素。SARS- COV-2突破肺血-气屏障,在器官间传播,诱导内皮细胞功能障碍, 多器官血栓栓塞ACE 2是SARS-Cov-2的高亲和力受体,具有TMPRSS 2裂解, 使核聚变成为可能然而,ACE 2和TMPRSS并不是在所有SARS-Cov-2感染的器官中共表达。 我们发现人血小板表达ACE 2和TMPRSS,结合SARS-Cov-2刺突蛋白, 内化ACE 2-刺突蛋白复合物。SARS-Cov-2 RNA在血小板内积累。 原发性高血压中血小板活化,转基因肾素表达刺激纤维化, 凝血,并且抑制凝血阻断肾素纤维化。直接的肾素抑制剂阿利吉仑阻断 高血压动物中的血栓形成,因此肾素嵌入凝血中以引发血栓栓塞性疾病。 我们发现释放前肾素的细胞刺激爆炸性血小板活化,但以一种独特的方式, 的激活是非常延迟的,激活总是最大的。从机制上讲,前肾素与 静止血小板促进细胞内磷脂酰丝氨酸逃逸到血小板表面。 磷脂酰丝氨酸组织tenase和凝血酶原酶凝血复合物,形成因子Xa, 爆发性激活血小板PAR 1凝血酶受体的凝血酶。阿利吉仑消除磷脂酰丝氨酸 表达、凝血酶形成和血栓形成。这使肾素成为一种新型的直接血小板激动剂。 显示表面磷脂酰丝氨酸的血小板被内皮细胞吞噬而迅速清除, 肝、肺和脾的网状内皮系统的血管周围巨噬细胞。我们推测 高血压和肾素表达促进血小板上的磷脂酰丝氨酸展示,启动凝血, 血小板活化,而且还促进快速血小板清除。我们假设,这将SARS-Cov-2内化为 细胞本身不需要表达ACE 2或TMPRSS 2。 目标1。检验肾素活化血小板是SARS-Cov-2进入 网状内皮系统的内皮细胞和巨噬细胞。 目标二。检验体内肾素刺激血小板周转引入SARS-Cov-2的假设 将假型慢病毒-血小板复合物导入不同器官。 该项目将建立高血压和SARS-Cov-2感染之间的功能联系, 肾素活化的血小板作为新的SARS-Cov-2进入载体,并确定了改变血小板清除的基础, 高血压小鼠。这为阿利吉仑用于使高血压正常化提供了转化基础 COVID-19的风险,阐明了抑制SARS-Cov-2器官感染和损伤的新方法, 建立循环血小板ACE 2表达作为衡量COVID-19多器官损伤风险的指标。
英文摘要
Hypertension, for unknown reasons, is a primary co-morbidity risk factor for poor COVID-19 outcomes. SARS- Cov-2 breaches the lung blood-air barrier to spread among organs inducing endothelial cell dysfunction and multi-organ thromboembolism. ACE2 is the high affinity receptor for SARS-Cov-2 with TMPRSS2 cleavage then enabling fusion. However, ACE2 and TMPRSS are not co-expressed by all SARS-Cov-2 infected organs. We discovered human platelets express ACE2 and TMPRSS, bind SARS-Cov-2 spike protein, and internalize ACE2-spike protein complexes. SARS-Cov-2 RNA accumulates within platelets. Platelets are activated in essential hypertension, transgenic renin expression stimulates fibrosis and coagulation, and inhibition of coagulation blocks renin fibrosis. The direct renin inhibitor Aliskiren blocks thrombosis in hypertensive animals, so renin intercalates into coagulation to initiate thromboembolic disease. We discovered cells releasing prorenin stimulate explosive platelet activation, but in a unique way; the onset of activation was very delayed, and activation was always maximal. Mechanistically, prorenin interacted with quiescent platelets promoting escape of intracellular phosphatidylserine onto the platelet surface. Phosphatidylserine organizes tenase and prothrombinase coagulation complexes, forming factor Xa and then thrombin that explosively activated the platelet PAR1 thrombin receptor. Aliskiren abolished phosphatidylserine expression, thrombin formation, and thrombosis. This establishes renin as a novel, direct platelet agonist. Platelets displaying surface phosphatidylserine are rapidly cleared by engulfment by endothelial cells and perivascular macrophages of the reticuloendothelial system of liver, lung, and spleen. We postulate hypertension and renin expression promotes phosphatidylserine display on platelets, initiating coagulation and platelet activation, but also promoting rapid platelet clearance. This, we postulate, internalizes SARS-Cov-2 into cells that need not express ACE2 or TMPRSS2, themselves. Aim 1. Test the hypothesis that renin-activated platelets are entry vectors for SARS-Cov-2 into endothelial cells and macrophages of the reticuloendothelial system. Aim 2. Test the hypothesis renin-stimulated platelet turnover in vivo introduces SARS-Cov-2 pseudotyped lentivirus-platelet complexes into diverse organs. This project will establish a functional connection between hypertension and SARS-Cov-2 infection, identify renin activated platelets as novel SARS-Cov-2 entry vectors, and define a basis for altered platelet clearance in renin-clamped hypertensive mice. This provides a translational basis for Aliskiren use to normalize hypertension risk in COVID-19, elucidates novel approaches to suppress SARS-Cov-2 organ infection and damage, and establish circulating platelet ACE2 expression as a measure of risk for COVID-19 multi-organ damage.
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Hypertension augmented COVID-19 through renin-induced internalization of platelet-ACE2 / SARS-Cov-2 complexes
  • 批准号:
    10275251
  • 项目类别:
  • 资助金额:
    $57.23万
  • 财政年份:
    2021
  • 负责人:
    Thomas M McIntyre
  • 依托单位:
Pilot Project Core
  • 批准号:
    10397511
  • 项目类别:
  • 资助金额:
    $8.96万
  • 财政年份:
    2016
  • 负责人:
    Thomas M McIntyre
  • 依托单位:
Core D: Pilot Project Core
  • 批准号:
    8977737
  • 项目类别:
  • 资助金额:
    $18.78万
  • 财政年份:
    2016
  • 负责人:
    Thomas M McIntyre
  • 依托单位:
Pilot Project Core
  • 批准号:
    10056026
  • 项目类别:
  • 资助金额:
    $8.96万
  • 财政年份:
    2016
  • 负责人:
    Thomas M McIntyre
  • 依托单位:
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