Acute Hyperglycemia Exacerbates Hemorrhagic Transformation after Embolic Stroke and Reperfusion with tPA: A Possible Role of TXNIP-NLRP3 Inflammasome.
Acute Hyperglycemia Exacerbates Hemorrhagic Transformation after Embolic Stroke and Reperfusion with tPA: A Possible Role of TXNIP-NLRP3 Inflammasome.
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DOI：
10.1016/j.jstrokecerebrovasdis.2021.106226
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发表时间：
2022-03
期刊：
影响因子：
--
通讯作者：
Ishrat T
中科院分区：
文献类型：
--
作者：
Salman M;Ismael S;Li L;Ahmed HA;Puchowicz MA;Ishrat T
急性高血糖（HG）加重脑卒中后再灌注损伤。我们最近的研究表明，急性HG上调硫氧还蛋白相互作用蛋白（TXNIP）的表达，从而在缝合缺血性脑卒中模型中诱导炎症和神经血管损伤。本研究的目的是研究急性HG对txnip相关神经血管损伤的影响，在更具临床相关性的栓塞性卒中和静脉组织纤溶酶原激活剂（IV-tPA）再灌注的小鼠模型中。采用20%葡萄糖腹腔注射的方法，诱导成年雄性小鼠发生HG。随后是栓塞性大脑中动脉闭塞（eMCAO），在栓塞3h后给予或不给予静脉注射组织型纤溶酶原激活剂（IV-tPA: 10 mg/kg）。在eMCAO后24小时评估脑梗死、水肿、血红蛋白含量、基质金属蛋白酶（MMP-9）、血管内皮生长因子A （VEGFA）、紧密连接蛋白（claudin-5、occludened和zoonula occludens-1）、TXNIP和nod样受体蛋白3 (NLRP3)-炎性体活化的表达。单独HG显著增加eMCAO后脑内TXNIP，这与出血转化加剧（HT；通过血红蛋白含量测量）有关。HG组IV-tPA有减小梗死面积的趋势，但eMCAO后HT加重，提示HG降低了IV-tPA的治疗效果。此外，HG和tpa -再灌注组之间MMP-9、VEGFA、连接蛋白的表达和NLRP3炎症小体的活化没有显着差异。目前的研究结果表明，TXNIP在eMCAO后高血糖条件下HT的发生中具有潜在作用。血管TXNIP在HG/ tpa诱导的脑卒中后神经血管损伤中的确切作用有待进一步研究。
Acute hyperglycemia (HG) exacerbates reperfusion injury after stroke. Our recent studies showed that acute HG upregulates thioredoxin interacting protein (TXNIP) expression, which in turn induces inflammation and neurovascular damage in a suture ischemic stroke model. The aim of the present study was to investigate the effect of acute HG on TXNIP-associated neurovascular damage, in a more clinically relevant murine model of embolic stroke and intravenous tissue plasminogen activator (IV-tPA) reperfusion. HG was induced in adult male mice, by intraperitoneal injection of 20% glucose. This was followed by embolic middle cerebral artery occlusion (eMCAO), with or without intravenous-tissue plasminogen activator (IV-tPA: 10 mg/kg) given 3h post embolization. Brain infarction, edema, hemoglobin content, expression of matrix metalloproteinase (MMP-9), vascular endothelial growth factor A (VEGFA), tight junction proteins (claudin-5, occluding, and zonula occludens-1), TXNIP, and NOD-like receptor protein3 (NLRP3)-inflammasome activation were evaluated at 24h after eMCAO. HG alone significantly increased TXNIP in the brain after eMCAO, and this was associated with exacerbated hemorrhagic transformation (HT; as measured by hemoglobin content). IV-tPA in HG conditions showed a trend to decrease infarct volume, but worsened HT after eMCAO, suggesting that HG reduces the therapeutic efficacy of IV-tPA. Further, HG and tPA-reperfusion did not show significant differences in expression of MMP-9, VEGFA, junction proteins, and NLRP3 inflammasome activation between the groups. The current findings suggest a potential role for TXNIP in the occurrence of HT in hyperglycemic conditions following eMCAO. Further studies are needed to understand the precise role of vascular TXNIP on HG/tPA-induced neurovascular damage after stroke.
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