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

不明原因的高血压是新冠肺炎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间扩散导致内皮细胞功能障碍 多器官血栓栓塞症。ACE2是TMPRSS2裂解的SARS-CoV-2的高亲和力受体 使聚变成为可能。然而，并不是所有SARS-CoV-2感染的器官都共表达ACE2和TMPRSS。 我们发现，人血小板表达ACE2和TMPRSS，结合SARS-CoV-2刺突蛋白，并 内化ACE2-Spike蛋白复合体。SARS-CoV-2RNA积聚在血小板内。 高血压患者血小板被激活，转基因肾素表达刺激纤维化和 凝血和抑制凝血可阻断肾素纤维化。直接肾素抑制剂Aliskiren阻断 高血压动物中的血栓形成，因此肾素插入凝血中，引发血栓栓塞症。 我们发现，释放前肾素的细胞刺激了血小板的爆炸性激活，但方式独特； 激活的时间非常延迟，而激活总是最大的。从机制上讲，Prorenin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。 磷脂酰丝氨酸组织肌腱酶和凝血酶原酶凝固复合体，形成Xa因子，然后 能爆炸性激活血小板PAR1凝血酶受体的凝血酶。阿利吉伦废止磷脂酰丝氨酸 表达、凝血酶形成和血栓形成。这确立了肾素是一种新的、直接的血小板激动剂。 显示表面磷脂酰丝氨酸的血小板被内皮细胞吞噬后迅速清除，并 肝、肺、脾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血小板上磷脂酰丝氨酸的显示，启动凝血和 激活血小板，还能促进血小板快速清除。我们推测，这会将SARS-CoV-2内化为 不需要表达ACE2或TMPRSS2的细胞本身。 目的1.验证肾素激活的血小板是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。 目的2.验证肾素刺激体内血小板更新的假说引入SARS-CoV-2 假型慢病毒-血小板复合体进入不同的器官。 该项目将在高血压和SARS-CoV-2感染之间建立功能联系，确定 肾素激活的血小板作为新的SARS-CoV-2进入载体，并定义了改变血小板清除的基础 肾素夹闭的高血压小鼠。这为阿利吉仑用于使高血压正常化提供了翻译基础 新冠肺炎的风险，阐明了抑制SARS-CoV-2器官感染和损害的新方法，以及 建立循环血小板血管紧张素转换酶2表达作为新冠肺炎多器官损害风险的测量方法。

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.