Abstract
Background and PurposeRecent studies have shown that several proteins, including Axl, are related to hemorrhagic transformation (HT) following intravenous thrombolysis by affecting blood-brain barrier (BBB) function. However, the effects of these proteins on BBB function have been studied primarily in animal models. In this study, we aimed to identify serum protein markers that predict HT following intravenous thrombolysis in patients with acute ischemic stroke (AIS) and verify whether these serum proteins regulate BBB function and HT in animal stroke models.MethodsFirst, 118 AIS patients were enrolled in this study, including 52 HT patients and 66 non-HT patients. In Step 1, baseline serum levels of Axl, angiopoietin-like 4, C-reactive protein, ferritin, hypoxia-inducible factor-1 alpha, HTRA2, Lipocalin2, matrix metallopeptidase 9, platelet-derived growth factor-BB, and tumor necrosis factor alpha were measured using a quantitative cytokine chip. Next, sequence mutations and variations in genes encoding the differentially expressed proteins identified in Step 1 and subsequent function-related proteins were detected. Finally, we verified whether manipulation of differentially expressed proteins affected BBB function and HT in a hyperglycemia-induced rat stroke model.ResultsSerum Axl levels were significantly lower in the HT group than in the non-HT group; none of the other protein markers differed significantly between the two groups. Genetic testing revealed that sequence variations of GAS6 (the gene encoding the Axl ligand)-derived long non-coding RNA, GAS6-AS1, were significantly correlated with an increased risk of HT after intravenous thrombolysis. In animal studies, administration of recombinant GAS6 significantly reduced brain infarction and neurological deficits and attenuated BBB disruption and HT.ConclusionsLower serum Axl levels, which may result from sequence variations in GAS6-AS1, are correlated with an increased risk of HT after intravenous thrombolysis in stroke patients. Activation of the Axl signaling pathway by the GAS6 protein may serve as a therapeutic strategy to reduce HT in AIS patients.
Highlights
Stroke is a major cause of disability and death worldwide [1, 2]
Serum Proteins in hemorrhagic transformation (HT) and Non-HT Groups The comparison of Axl, ANGPTL4, CRP, ferritin, HIF-1a, HTRA2, lipocalin2, MMP-9, PDGF-BB, and TNF-a levels revealed that Axl levels were significantly lower in the HT group compared with the non-HT group (P
We demonstrated that lower levels of Axl were associated with greater opportunities for HT, which indicated the protective effect of Axl on blood-brain barrier (BBB) function
Summary
Stroke is a major cause of disability and death worldwide [1, 2]. Recombinant tissue plasminogen activator (rt-PA) is currently the most effective treatment for acute ischemic stroke (AIS) [3]. Hemorrhagic transformation (HT), a major complication of rt-PA therapy, increases life-threatening risk and contributes to adverse events in patients with AIS [4, 5]. The mechanism of HT after thrombolysis is complicated, and disruption of the blood-brain barrier (BBB) plays an important role in this process [6, 7]. Recent studies have shown that several proteins, including Axl, are related to hemorrhagic transformation (HT) following intravenous thrombolysis by affecting blood-brain barrier (BBB) function. The effects of these proteins on BBB function have been studied primarily in animal models. We aimed to identify serum protein markers that predict HT following intravenous thrombolysis in patients with acute ischemic stroke (AIS) and verify whether these serum proteins regulate BBB function and HT in animal stroke models
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