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: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 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/10490385
• 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; COVID-19 risk; Cardiovascular system; Cells; Closure by clamp; Coagulation Process; Complex; Consumption; Denervation; Deposition; Disease; Eating; Endothelial Cells; Endothelium; Essential Hypertension; F2R gene; FDA approved; Factor Xa; Fibrin; Fibrinolytic Agents; 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; Pulmonary alveolar structure; 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; hypertensive; in vivo; inhibitor; 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

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.

由于未知原因，高血压是导致 COVID-19 预后不良的主要共病风险因素。非典- Cov-2突破肺血气屏障在器官之间传播，引起内皮细胞功能障碍和 多器官血栓栓塞。 ACE2 是 SARS-Cov-2 的高亲和力受体，TMPRSS2 裂解 实现融合。然而，ACE2 和 TMPRSS 并非在所有 SARS-Cov-2 感染的器官中共同表达。 我们发现人类血小板表达 ACE2 和 TMPRSS，结合 SARS-Cov-2 刺突蛋白，并且 内化 ACE2-刺突蛋白复合物。 SARS-Cov-2 RNA 在血小板内积聚。 原发性高血压中血小板被激活，转基因肾素表达刺激纤维化和 凝血，抑制凝血可阻止肾素纤维化。直接肾素抑制剂阿利吉仑阻断 高血压动物发生血栓，因此肾素插入凝血过程中引发血栓栓塞性疾病。 我们发现释放肾素原的细胞会刺激血小板的爆炸性活化，但以一种独特的方式；发作 激活非常延迟，并且激活始终是最大的。从机制上讲，肾素原与 静止的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，然后 爆炸性激活血小板 PAR1 凝血酶受体的凝血酶。阿利吉仑废除磷脂酰丝氨酸 表达、凝血酶形成和血栓形成。这确立了肾素作为一种新型的直接血小板激动剂的地位。 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。我们假设 高血压和肾素表达促进磷脂酰丝氨酸在血小板上的展示，启动凝血和 血小板活化，还能促进血小板快速清除。我们假设，这将 SARS-Cov-2 内化为 细胞本身不需要表达 ACE2 或 TMPRSS2。 目标 1. 检验肾素激活血小板是 SARS-Cov-2 进入载体的假设 网状内皮系统的内皮细胞和巨噬细胞。 目标 2. 检验体内肾素刺激血小板更新引入 SARS-Cov-2 的假设 假型慢病毒-血小板复合物进入不同的器官。 该项目将建立高血压与 SARS-Cov-2 感染之间的功能联系，确定 肾素激活血小板作为新型 SARS-Cov-2 进入载体，并定义了改变血小板清除率的基础 肾素钳制高血压小鼠。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，阐明抑制 SARS-Cov-2 器官感染和损害的新方法，以及 建立循环血小板 ACE2 表达作为 COVID-19 多器官损伤风险的衡量标准。