Abstract：
Hypertension causes platelet activation and adhesion in the brain resulting in glial activation and neuroinflammation. Further, activation of Angiotensin-Converting Enzyme 2/Angiotensin (1-7)/Mas Receptor (ACE2/Ang (1-7)/MasR) axis of central Renin-Angiotensin System (RAS), is known to reduce glial activation and neuroinflammation, thereby exhibiting anti-hypertensive and anti-neuroinflammatory properties. Therefore, in the present study, the role of ACE2/Ang (1-7)/MasR axis was studied on platelet-induced glial activation and neuroinflammation using Diminazene Aceturate (DIZE), an ACE2 activator, in astrocytes and microglial cells as well as in rat model of hypertension. We found that the ACE2 activator DIZE, independently of its BP-lowering properties, efficiently prevented hypertension-induced glial activation, neuroinflammation, and platelet CD40-CD40L signaling via upregulation of ACE2/Ang (1-7)/MasR axis. Further, DIZE decreased platelet deposition in the brain by reducing the expression of adhesion molecules on the brain endothelium. Activation of ACE2 also reduced hypertension-induced endothelial dysfunction by increasing eNOS bioavailability. Interestingly, platelets isolated from hypertensive rats or activated with ADP had significantly increased sCD40L levels and induced significantly more glial activation than platelets from DIZE treated group. Therefore, injection of DIZE pre-treated ADP-activated platelets into normotensive rats strongly reduced glial activation compared to ADP-treated platelets. Moreover, CD40L-induced glial activation, CD40 expression, and NFкB-NLRP3 inflammatory signaling are reversed by DIZE. Furthermore, the beneficial effects of ACE2 activation, DIZE was found to be significantly blocked by MLN4760 (ACE2 inhibitor) as well as A779 (MasR antagonist) treatments. Hence, our study demonstrated that ACE2 activation reduced the platelet CD40-CD40L induced glial activation and neuroinflammation, hence imparted neuroprotection.
摘要：
高血压引起脑中的血小板活化和粘附,导致神经胶质活化和神经炎症。Further,激活血管紧张素转换酶2/血管紧张素（1-7）/MAS受体（ACE2/Ang（1-7）/MasR）中央肾素-血管紧张素系统（RAS），已知可以减少神经胶质激活和神经炎症，从而表现出抗高血压和抗神经炎性质。因此,在本研究中，ACE2/Ang(1-7)/MasR轴的作用在血小板诱导的胶质细胞活化和神经炎症中使用醋酸二嗪(DIZE),ACE2激活剂，星形胶质细胞和小胶质细胞以及高血压大鼠模型。我们发现ACE2激活剂DIZE,独立于其降低BP的特性，有效预防高血压诱导的神经胶质激活，神经炎症，和通过上调ACE2/Ang(1-7)/MasR轴的血小板CD40-CD40L信号传导。Further,DIZE通过减少脑内皮上粘附分子的表达来减少血小板在脑中的沉积。ACE2的激活还通过增加eNOS的生物利用度来减少高血压诱导的内皮功能障碍。有趣的是,与DIZE治疗组的血小板相比,从高血压大鼠分离的或用ADP活化的血小板显著增加了sCD40L水平,并诱导了显著更多的胶质细胞活化.因此,与ADP处理的血小板相比，将DIZE预处理的ADP激活的血小板注射到正常血压的大鼠中大大降低了神经胶质的激活。此外，CD40L诱导的胶质细胞活化，CD40表达，NFκB-NLRP3炎症信号被DIZE逆转。此外，ACE2激活的有益效果，发现DIZE被MLN4760(ACE2抑制剂)以及A779(MasR拮抗剂)治疗显著阻断。因此，我们的研究表明，ACE2激活降低了血小板CD40-CD40L诱导的胶质细胞活化和神经炎症，因此赋予神经保护。
