Abstract
AimsThe 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.Methods355 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.ResultsDuring 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 < .001, OR 7.607; rs75336000, P = .044, OR 2.503) were selectively enriched in the PH patients. Interestingly, a missense variant of GPR124 (rs75336000, c.3587G>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.ConclusionVariants 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.
Highlights
Our results showed that compared to the non-parenchymal hematoma (PH) patients, five genetic variants belonging to Wnt7A and GPR124 were selectively enriched in the PH patients, including two singlenucleotide polymorphisms (SNPs) of WNT7A and three SNPs of GPR124 (Table 2)
We have extensively examined the association of genetic variants of canonical Wnt signaling pathway with the risk of hemorrhagic transformation (HT) following recombinant tissue-type plasminogen activator (rt-PA)-mediated thrombolysis therapy in a cohort of Chinese acute ischemic stroke (AIS) patients
We identified that several genetic variants of WNT7A and GPR124 are associated with risk of parenchymal hematoma (PH), the clinically detrimental form of HT
Summary
80% of strokes are caused by thrombotic occlusion of brain arteries with subsequent cerebral ischemia.[1,2] The only pharmacological intervention approved by the US Food and Drug Administration (FDA) for acute ischemic stroke (AIS) is the thrombolytic agent recombinant tissue-type plasminogen activator (rt-PA).[3,4,5,6] rt-PA treatment significantly increases the risk of hemorrhagic transformation (HT).[7,8,9,10] As a major complication of thrombolytic therapy, HT especially the parenchymal hematoma (PH) is associated with significantly increased stroke morbidity and mortality.[7,11] Currently, the risk factors underlying HT pathogenesis remain unclear and clinically amenable biomarkers are urgently needed to better predict the risk and severity of HT. We demonstrated that following acute cerebral ischemia/reperfusion injury in mice, decreased canonical Wnt signaling activity in Gpr[124] knockout brain endothelium led to exacerbation of BBB disruption and severe ICH, resembling severe PH in human strokes.[21] canonical Wnt signaling activity regulated rtPA-induced HT in rodent ischemic stroke models.[44,45,46] the impact of canonical Wnt signaling pathway on human BBB integrity and HT after ischemic stroke remains completely unexplored. We aimed to identify the association of the canonical Wnt signaling with risk of HT in AIS patients by assessing sequence variations in Wnt signaling genes and determine their effects on the activity of cellular Wnt signaling
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