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

基本信息

批准号：
10275251
负责人：
Thomas M McIntyre
金额：
$ 57.23万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-20 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10275251
关键词：
2019-nCoV ACE2 Acute Affinity Age Agonist Aldosterone Angiotensinogen Animals Autopsy Binding Blood Blood Circulation Blood Coagulation Disorders Blood Platelets Blood coagulation Blood-Air Barrier COVID-19 COVID-19 pandemic COVID-19 patient COVID-19 prognosis Cardiovascular system Cells Cleaved cell Closure by clamp Coagulation Process Complex Consumption Denervation Deposition Disease Eating Endothelial Cells Endothelium Essential Hypertension F2R gene FDA approved Factor Xa Fibrin Fibrosis Functional disorder Genetic German population Heart Injuries Human Hypertension Inactive Renin Incidence Infection Inflammation Kidney Lentivirus Liver Lung Lung diseases Mass Spectrum Analysis Measures Mediating Megakaryocytes Membrane Mus Nervous System Trauma Organ Outcome Pathway interactions Patients Pattern Pepstatins Peptide Hydrolases Pharmaceutical Preparations Phosphatidylserines Plasma Platelet Activation Platelet aggregation Proteins Proteolysis RNA Rattus Renin Reporter Reticuloendothelial System Risk Risk Factors Role Route SARS-CoV-2 infection SARS-CoV-2 spike protein Severe Acute Respiratory Syndrome Signal Transduction Site Spleen Surface System TMPRSS2 gene Testing Therapeutic Thrombin Thrombin Receptor Thrombocytopenia Thromboembolism Thromboplastin Thrombosis Thrombus Tissues Transgenic Animals Transgenic Organisms Tropism Viral Virus aliskiren cell injury comorbidity factor IXa-factor VIIIa heart damage in vivo inhibitor/antagonist innovation liver injury lung injury macrophage multiorgan damage novel novel strategies particle prophylactic prorenin receptor protein complex receptor renal damage respiratory thrombotic thrombotic complications uptake vector

项目摘要

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.

出于未知原因，高血压是较差的共同性结果的主要合并症风险因素。 sars- COV-2违反了肺血液屏障，以在诱导内皮细胞功能障碍的器官之间传播多器官血栓栓塞。 ACE2是用TMPRSS2裂解的SARS-COV-2的高亲和力受体启用融合。但是，所有SARS-COV-2感染器官并未共同表达ACE2和TMPRS。我们发现人血小板表达ACE2和TMPRS，结合SARS-COV-2峰值蛋白，以及内部化ACE2尖峰蛋白复合物。 SARS-COV-2 RNA在血小板中积聚。血小板在必需的高血压，转基因肾素表达中被激活，刺激纤维化和凝结和抑制凝血阻断肾素纤维化。直接肾素抑制剂Aliskiren块高血压动物的血栓形成，因此肾素插入凝结以启动血栓栓塞疾病。我们发现释放prorenin的细胞刺激了爆炸性的血小板激活，但以独特的方式刺激。发作激活非常延迟，并且激活始终是最大的。从机械上讲，prorenin与静止的血小板促进细胞内磷脂酰丝氨酸逃脱到血小板表面。磷脂酰丝氨酸组织Tenase和凝血酶凝结酶凝结复合物，形成因子XA，然后是凝血酶爆炸性地激活了血小板PAR1凝血酶受体。阿利基林废除了磷脂酰丝氨酸表达，凝血酶形成和血栓形成。这将肾素确立为一种新颖的直接血小板激动剂。内皮细胞和肝，肺和脾脏网状内皮系统的血管周巨噬细胞。我们假设高血压和肾素表达促进血小板上的磷脂酰丝氨酸显示，引发凝结和血小板激活，但也促进了快速血小板清除率。我们假设这将SARS-COV-2内部化为不需要表达ACE2或TMPRSS2的细胞本身。目的1。检验肾素激活血小板是SARS-COV-2的入口向量的假设网状内皮系统的内皮细胞和巨噬细胞。 AIM 2。在体内测试假设肾素刺激的血小板周转率引入SARS-COV-2 伪造的慢病毒 - 细胞表复合物成各种器官。该项目将在高血压和SARS-COV-2感染之间建立功能连接，确定肾素激活血小板作为新型SARS-COV-2进入向量，并定义了改变血小板清除率的基础肾素钳制的高血压小鼠。这为Aliskiren使用以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器官感染和损害的新型方法，以及建立循环血小板ACE2表达，以衡量COVID-19多器官损伤的风险。