Variants of WNT7A and GPR124 are associated with hemorrhagic transformation following intravenous thrombolysis in ischemic stroke

Autor: Wenlan Liu, Lilong Lin, Zhen-Ni Guo, Song Ta, Peng Zhang, Junlei Chang, Qingquan Gu, Feng-E Li, Zhihuan Li, Xianfang Rong, Yi Yang, Hang Jin, Chenqing Zheng, Yuan Zhang
Rok vydání: 2020
Předmět:
blood‐brain barrier
signaling pathway
Male
0301 basic medicine
FZD4
medicine.medical_treatment
single‐nucleotide polymorphism
Pharmacology
Blood–brain barrier
Polymorphism
Single Nucleotide
Brain Ischemia
Receptors
G-Protein-Coupled
03 medical and health sciences
0302 clinical medicine
Fibrinolytic Agents
Physiology (medical)
ischemic stroke
medicine
Humans
Thrombolytic Therapy
Pharmacology (medical)
Stroke
Aged
Cerebral Hemorrhage
Intracerebral hemorrhage
business.industry
Wnt signaling pathway
Genetic Variation
Original Articles
Thrombolysis
Middle Aged
medicine.disease
intracerebral hemorrhage
Wnt Proteins
Psychiatry and Mental health
030104 developmental biology
medicine.anatomical_structure
WNT7A
Original Article
Administration
Intravenous
Female
Signal transduction
business
030217 neurology & neurosurgery
Zdroj: CNS Neuroscience & Therapeutics
ISSN: 1755-5949
1755-5930
DOI: 10.1111/cns.13457
Popis: Aims The canonical Wnt signaling pathway plays an essential role in blood‐brain barrier integrity and intracerebral hemorrhage in preclinical stroke models. Here, we sought to explore the association between canonical Wnt signaling and hemorrhagic transformation (HT) following intravenous thrombolysis (IVT) in acute ischemic stroke (AIS) patients as well as to determine the underlying cellular mechanisms. Methods 355 consecutive AIS patients receiving IVT were included. Blood samples were collected on admission, and HT was detected at 24 hours after IVT. 117 single‐nucleotide polymorphisms (SNPs) of 28 Wnt signaling genes and exon sequences of 4 core cerebrovascular Wnt signaling components (GPR124, RECK, FZD4, and CTNNB1) were determined using a customized sequencing chip. The impact of identified genetic variants was further studied in HEK 293T cells using cellular and biochemical assays. Results During the study period, 80 patients experienced HT with 27 parenchymal hematoma (PH). Compared to the non‐PH patients, WNT7A SNPs (rs2163910, P = .001, OR 2.727; rs1124480, P = .002, OR 2.404) and GPR124 SNPs (rs61738775, P = .012, OR 4.883; rs146016051, P A) identified in the PH patients resulted in a single amino acid alteration (p.Cys1196Tyr) in the intracellular domain of GPR124. This variant substantially reduced the activity of WNT7B‐induced canonical Wnt signaling by decreasing the ability of GPR124 to recruit cytoplasmic DVL1 to the cellular membrane. Conclusion Variants of WNT7A and GPR124 are associated with increased risk of PH in patients with AIS after intravenous thrombolysis, likely through regulating the activity of canonical Wnt signaling.
Databáze: OpenAIRE
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