Inhibition of PAI (Plasminogen Activator Inhibitor)-1 Improves Brain Collateral Perfusion and Injury After Acute Ischemic Stroke in Aged Hypertensive Rats.
Inhibition of PAI (Plasminogen Activator Inhibitor)-1 Improves Brain Collateral Perfusion and Injury After Acute Ischemic Stroke in Aged Hypertensive Rats.
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DOI：
10.1161/strokeaha.118.022056
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发表时间：
2018-08
期刊：
影响因子：
8.3
通讯作者：
Cipolla MJ
中科院分区：
文献类型：
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作者：
Chan SL;Bishop N;Li Z;Cipolla MJ
老年和高血压是卒中人群中普遍存在的并存疾病，与侧支循环状态差和卒中预后恶化有关。然而，这些条件影响卒中结局的潜在机制尚不清楚。我们研究了在衰老和高血压中增加的纤溶酶原激活物抑制物-1(PAI-1)对脑血管炎症因子表达和血流的作用，这可能导致更糟糕的中风预后。老年(~50周)自发性高血压大鼠(SHR)和青年(~18周)自发性高血压大鼠(SHR)采用大脑中动脉闭塞(MCAO，2hr)和再灌流(2hr)加或不加PAI-1抑制剂TM5441治疗的缺血模型。用多点激光多普勒测量大脑中动脉和侧支循环灌注区的变化。用分离的加压软脑膜吻合小动脉(LMA)研究TM5441的反应性。用2，3，5-三苯基四氮唑染色和定量免疫组织化学方法检测脑内淀粉样蛋白-β−42、纤溶酶原激活物-1和血红蛋白。采用双抗体夹心法检测循环炎症因子。两组MCAO期间脑血流变化相似，均有较差的侧支循环和不完全再灌流。然而，老年自发性高血压大鼠较青年自发性高血压大鼠有更大的脑损伤(41±2vs23±2%，p<；0.05)以及脑内淀粉样蛋白β−42和循环氧化低密度脂蛋白的沉积增加。50%的老年自发性高血压大鼠脑内可见红细胞聚集和出血，而青年自发性高血压大鼠则未见。老年自发性高血压大鼠这一亚组循环PAI-1升高(16±3vs6±2 ng/ml，p<；0.05)。TM5441抑制PAI-1可改善脑损伤，但不影响出血。TM5441使侧支循环血流灌注量增加38±7%，使LMA扩张44±10%，其作用可被一氧化氮合酶抑制所消除。老年自发性高血压大鼠损伤加重可能与侧支循环灌注不良、出血转化、淀粉样蛋白β−42升高和氧化应激有关。PAI-1抑制减少了两组自发性高血压患者的脑梗塞，这可能部分是由于侧支循环灌注量增加。
Aging and hypertension, co-morbidities prevalent in the stroke population, are associated with poor collateral status and worsened stroke outcome. However, underlying mechanisms by which these conditions affect stroke outcome are not clear. We studied the role of plasminogen activator inhibitor-1 (PAI-1) that is increased in aging and hypertension on brain and vascular expression of inflammatory factors and perfusion that may contribute to worse stroke outcomes. Aged (~50 weeks) and young (~18 weeks) spontaneously hypertensive rats (SHR) were subjected to ischemia by middle cerebral artery occlusion (MCAO, 2hr) and reperfusion (2hr) with or without treatment with the PAI-1 inhibitor TM5441. Changes in MCA and collateral perfusion territories were measured by multisite laser Doppler. Reactivity to TM5441 was studied using isolated and pressurized leptomeningeal anastomotic arterioles (LMAs). Brain injury was determined by 2,3,5-triphenyltetrazolium staining and quantitative immunohistochemistry of amyloid-β−42, PAI-1, and hemoglobin. Circulating inflammatory factors were measured by ELISA. Changes in cerebral blood flow during MCAO were similar between groups, with both having poor collateral perfusion and incomplete reperfusion. However, aged SHR had greater brain injury vs. young (41±2 vs 23±2%, p<0.05) as well as increased brain deposition of amyloid-β−42 and circulating oxidized low-density lipoprotein. Erythrocyte aggregation and hemorrhage within the injured brain was observed in 50% of aged but no young SHR, with increased circulating PAI-1 in this subgroup of aged SHR (16±3 vs 6±2ng/ml, p<0.05). PAI-1 inhibition with TM5441 improved brain injury but did not affect hemorrhage. TM5441 increased collateral perfusion by 38±7% and dilated LMAs by 44±10%, which was abolished by nitric oxide synthase inhibition. Increased injury in aged SHR appeared to be related to poor collateral perfusion, hemorrhagic transformation, increased amyloid-β−42 and oxidative stress. PAI-1 inhibition reduced infarction in both groups of SHR that possibly due, in part, to increased collateral perfusion.