抑制 PAI-1（纤溶酶原激活物抑制剂-1）可改善老龄高血压大鼠急性缺血性脑卒中时的脑侧支循环灌注和损伤。
Inhibition of PAI (Plasminogen Activator Inhibitor)-1 Improves Brain Collateral Perfusion and Injury After Acute Ischemic Stroke in Aged Hypertensive Rats.
机构信息
From the Departments of Neurological Sciences (S.-L.C., N.B., Z.L., M.J.C.).
Obstetrics, Gynecology and Reproductive Sciences (M.J.C.).
出版信息
Stroke. 2018 Aug;49(8):1969-1976. doi: 10.1161/STROKEAHA.118.022056.
Background and Purpose- Aging and hypertension, comorbidities 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 PAI (plasminogen activator inhibitor)-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. Methods- Aged (≈50 weeks) and young (≈18 weeks) spontaneously hypertensive rats (SHR) were subjected to ischemia by middle cerebral artery occlusion (2 hours) and reperfusion (2 hours) with or without treatment with the PAI-1 inhibitor TM5441. Changes in middle cerebral artery and collateral perfusion territories were measured by multisite laser Doppler. Reactivity to TM5441 was studied using isolated and pressurized leptomeningeal anastomotic arterioles. 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. Results- Changes in cerebral blood flow during middle cerebral artery occlusion were similar between groups, with both having poor collateral perfusion and incomplete reperfusion. However, aged SHR had greater brain injury versus young (41±2 versus 23±2%, P<0.05) as well as increased brain deposition of amyloid-β-42 and circulating oxLDL (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 versus 6±2 ng/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 leptomeningeal anastomotic arterioles by 44±10%, which was abolished by nitric oxide synthase inhibition. Conclusions- Increased injury in aged SHR seemed 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.
背景与目的- 衰老和高血压是中风人群中常见的合并症，与侧支循环状态不良和中风预后恶化有关。然而，这些情况影响中风预后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 PAI-1（纤溶酶原激活物抑制剂-1）对脑和血管中炎症因子和灌注的表达的作用，这可能导致更差的中风结果。方法- 采用大脑中动脉闭塞（2 小时）和再灌注（2 小时）方法，使年龄较大（约 50 周）和年轻（约 18 周）自发性高血压大鼠（SHR）发生缺血，并用 PAI-1 抑制剂 TM5441 进行治疗或不进行治疗。通过多点激光多普勒测量大脑中动脉和侧支灌注区的变化。使用分离和加压软脑膜吻合小动脉来研究 TM5441 的反应性。通过 2,3,5-三苯基四氮唑染色和淀粉样蛋白-β-42、PAI-1 和血红蛋白的定量免疫组织化学来确定脑损伤。通过 ELISA 测量循环炎症因子。结果- 大脑中动脉闭塞期间的脑血流变化在两组之间相似，两组的侧支循环灌注均较差，再灌注不完全。然而，与年轻 SHR 相比，老年 SHR 的脑损伤更大（41±2 对 23±2%，P<0.05），以及大脑中淀粉样蛋白-β-42 和循环 oxLDL（氧化低密度脂蛋白）的沉积增加。在 50%的老年 SHR 中观察到损伤脑内的红细胞聚集和出血，而在该亚组的老年 SHR 中，循环 PAI-1 增加（16±3 对 6±2 ng/mL，P<0.05）。用 TM5441 抑制 PAI-1 可改善脑损伤，但不影响出血。TM5441 增加侧支循环灌注 38±7%，并使软脑膜吻合小动脉扩张 44±10%，这一作用被一氧化氮合酶抑制所消除。结论- 老年 SHR 中增加的损伤似乎与侧支循环灌注不良、出血性转化、淀粉样蛋白-β-42 增加和氧化应激有关。PAI-1 抑制减少了两组 SHR 的梗死，这可能部分是由于侧支循环灌注增加。
Zotero 插件