ArticleBlood2022
Thrombolytic tPA-induced hemorrhagic transformation of ischemic stroke is mediated by PKCβ phosphorylation of occludin.
Article in Blood, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers, 3 of them syntheses that pooled it.
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Who cites it
36 citing papers in PubMed, 3 syntheses or guidelines pooled it, 28 citations in OpenAlex.
- The use ofFrontiers in pharmacology · 2024Pooled it
- Association between uric acid and the risk of hemorrhagic transformation in patients with acute ischemic stroke: a systematic review and meta-analysis.Frontiers in neurology · 2024Pooled it
- Efficacy and Safety of Recombinant Human Prourokinase in Acute Ischemic Stroke: A Systematic Review and Meta-Analysis.Clinical and applied thrombosis/hemostasis : official journal of the International Academy of Clinical and Applied Thrombosis/HemostasisPooled it
- Inhibition of PKCγ phosphorylation protects against cerebral ischemia-reperfusion injury.Redox biology · 2026Article
- Endothelial tPA-dependent recruitment of microglia to vessels protects the blood-brain barrier after stroke.Fluids and barriers of the CNS · 2026Article
- Occludin modulates HIV and ischaemic stroke response via the mitochondrial antiviral signalling pathway.Brain : a journal of neurology · 2026Article
- Plat safeguards maternally aged oocytes against programmed cell death through activating the Erk1/2 pathway.Science China. Life sciences · 2026Article
- FDCA Attenuates Neuronal Ferroptosis and Reduces Hemorrhagic Transformation After Ischemic Stroke with High Glucose.Cellular and molecular neurobiology · 2026Article
- Occludin-mediated barrier dysfunction and its role in cardiovascular and cerebrovascular pathogenesis.Frontiers in cardiovascular medicine · 2026Review
- The latest research progress of ligustilide in the prevention and treatment of central nervous system disorders.Frontiers in pharmacology · 2026Review
- Occludin acts as a dynein adaptor regulating permeability and collateral angiogenesis.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Cellular and molecular mechanisms of thrombosis and thrombus-targeted thrombolytic strategies.Materials today. Bio · 2025Review
- Identification of post-translational modification-related biomarkers in ischemic stroke using bioinformatics and machine learning.Scientific reports · 2025Article
- Protein Kinase C Family: Structures, Biological Functions, Diseases, and Pharmaceutical Interventions.MedComm · 2025Review
- Endothelial NMMHC IIA dissociation from PAR1 activates the CREB3/ARF4 signaling in thrombin-mediated intracerebral hemorrhage.Journal of advanced research · 2025Article
- Salvianolic Acid A Activates Nrf2-Related Signaling Pathways to Inhibit Ferroptosis to Improve Ischemic Stroke.Molecules (Basel, Switzerland) · 2025Article
- Matrix metalloproteinase‑9 in hemorrhagic transformation after acute ischemic stroke (Review).Molecular medicine reports · 2025Review
- Deficiency in N-cadherin-Akt3 signaling impairs the blood-brain barrier.Cell reports · 2025Article
- PA System in the Pathogenesis of Ischemic Stroke.Arteriosclerosis, thrombosis, and vascular biology · 2025Review
- Shengui Sansheng San alleviates the worsening of blood-brain barrier integrity resulted from delayed tPA administration through VIP/VIPR1 pathway.Chinese medicine · 2025Article
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Authors and funding
11 authors at 3 institutions in 2 countries.
Funding
Abstract
The current standard of care for moderate to severe ischemic stroke is thrombolytic therapy with tissue plasminogen activator (tPA). Treatment with tPA can significantly improve neurologic outcomes; however, thrombolytic therapy is associated with an increased risk of intracerebral hemorrhage (ICH). The risk of hemorrhage significantly limits the use of thrombolytic therapy, and identifying pathways induced by tPA that increase this risk could provide new therapeutic options to extend thrombolytic therapy to a wider patient population. Here, we investigate the role of protein kinase Cβ (PKCβ) phosphorylation of the tight junction protein occludin during ischemic stroke and its role in cerebrovascular permeability. We show that activation of this pathway by tPA is associated with an increased risk of ICH. Middle cerebral artery occlusion (MCAO) increased phosphorylation of occludin serine 490 (S490) in the ischemic penumbra in a tPA-dependent manner, as tPA-/- mice were significantly protected from MCAO-induced occludin phosphorylation. Intraventricular injection of tPA in the absence of ischemia was sufficient to induce occludin phosphorylation and vascular permeability in a PKCβ-dependent manner. Blocking occludin phosphorylation, either by targeted expression of a non-phosphorylatable form of occludin (S490A) or by pharmacologic inhibition of PKCβ, reduced MCAO-induced permeability and improved functional outcome. Furthermore, inhibiting PKCβ after MCAO prevented ICH associated with delayed thrombolysis. These results show that PKCβ phosphorylation of occludin is a downstream mediator of tPA-induced cerebrovascular permeability and suggest that PKCβ inhibitors could improve stroke outcome and prevent ICH associated with delayed thrombolysis, potentially extending the window for thrombolytic therapy in stroke.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.