Abstract
BackgroundDiabetes is known to be a main risk factor of post-stroke hemorrhagic transformation following recombinant tissue plasminogen activator (rt-PA) therapy. However, the mechanism through which diabetes exacerbates hemorrhagic transformation is insufficiently understood. We aimed to verify that CD147, the extracellular matrix metalloproteinase (MMP) inducer, played a vital role in the progress.MethodsWe performed middle cerebral artery occlusion on diabetic and non-diabetic rats, with or without rt-PA treatment, and then compared the glycosylation level of CD147, caveolin-1, MMPs activities, and blood-brain barrier (BBB) permeability. In vitro, tunicamycin treatment and genetic tools were used to produce non-glycosylated and lowly glycosylated CD147. An endogenous glucagon-like peptide-1 receptor (GLP-1R) agonist was used to downregulate the glycosylation of CD147 in vivo.ResultsCompared with non-diabetic rats, diabetic rats expressed higher levels of highly glycosylated CD147 in endothelium and astrocytes following rt-PA treatment accompanied by higher activity of MMPs and BBB permeability, in the middle cerebral artery occlusion model. Caveolin-1 was also overexpressed and co-localized with CD147 in astrocytes and endothelium in diabetic rats. In vitro, advanced glycation end products increased the expression of highly glycosylated CD147 in astrocytes and endothelial cells. Downregulating the glycosylation of CD147 lowered the activity of MMPs and promoted the expression of tight junction proteins. The expression of caveolin-1 in endothelial cells and astrocytes was not inhibited by tunicamycin, which revealed that caveolin-1 was an upstream of CD147. In vivo, GLP-1R agonist downregulated the glycosylation of CD147 and further reduced the activity of MMPs and protected the BBB in diabetic rats.ConclusionCD147 is essential for diabetes-associated rt-PA-induced hemorrhagic transformation, and downregulation of CD147 glycosylation is a promising therapy for neurovascular-unit repair after rt-PA treatment of patients with diabetes.
Highlights
Diabetes is known to be a main risk factor of post-stroke hemorrhagic transformation following recombinant tissue plasminogen activator therapy
Diabetes increases hemorrhagic transformation and blood-brain barrier (BBB) disruption after recombinant tissue plasminogen activator (rt-PA) treatment in cerebral ischemia We induced cerebral ischemia in rats by middle cerebral artery occlusion (MCAO) and treated it with rt-PA. rt-PA thrombolysis was effective in reducing brain infarct volume in both non-diabetic and diabetic rats, but significantly exacerbated intracerebral hemorrhagic transformation (HT) (Fig. 1a–c)
The results show that in diabetic rats, rt-PA therapy reduced the expression of these proteins in both the non-diabetes and diabetes groups, with the exception of zonula occludens-1 (ZO-1)
Summary
Diabetes is known to be a main risk factor of post-stroke hemorrhagic transformation following recombinant tissue plasminogen activator (rt-PA) therapy. Recombinant tissue plasminogen activator (rt-PA) has been certificated by multiple clinical trials as being a beneficial thrombolytic drug for the treatment of ischemic patients [4,5,6]; its clinical application requires caution due to the severe side effects which have been reported. 6% of ischemic stroke patients who have received rt-PA treatment will suffer symptomatic intracranial hemorrhagic transformation (HT), which can subsequently lead to severe disability and even death [7]. DM/stress hyperglycemia is found to be a main risk factor of rt-PA-induced symptomatic intracranial HT and a worse clinical outcome [8,9,10,11]. The aim of this study is to understand how DM/hyperglycemia exacerbates rt-PA-induced HT and investigate potential solutions for the application of rt-PA in DM patients with ischemic stroke
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