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Elevated glutamine triggers stroke risk in moyamoya disease via endothelial‐to‐mesenchymal transition, finds study

Discovery: Elevated glutamine triggers stroke risk in moyamoya disease via endMT transition
Glutamine promotes proliferation, migration, and EndMT through ITGB4 in HBMECs. (A) Kyoto Encyclopedia of Genes and Genomes enrichment analysis of HBMECs treated with glutamine. (B) RT-qPCR analysis of ITGB4 expression in HBMECs treated with glutamine. (C) Proliferation ability of HBMECs subjected to glutamine treatment and ITGB4 knockdown assessed by CCK8 assay. (D) Representative images of EdU assays in HBMECs subjected to glutamine treatment and ITGB4 knockdown. Each image represents three replicates. Scale bar, 10 µm. (E) Representative images (left) and histogram (right) of HBMEC migration, as determined via wound healing assays. Each image represents three replicates. Scale bar in white, 100 µm. (F) Representative images (left) and histogram (right) of the migration ability of HBMECs, as determined via transwell assays. Each image represents three replicates. Scale bar in black, 25 µm. (G) Western blot analysis (left) and the histograms (right) of Vimentin, αSMA, VE-cadherin, CD31, and ITGB4 in HBMECs subjected to different treatments. **p < 0.01, ***p < 0.001, ****p < 0.0001. EndMT, endothelial-to-mesenchymal transition; HBMECs, human brain microvascular endothelial cells. Credit: MedComm (2024). DOI: 10.1002/mco2.525

A study appearing in MedComm has been led by Dr. Jizong Zhao, Dr. Dong Zhang, and Dr. Peicong Ge (Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University and Department of Neurosurgery, Beijing Hospital). The team presents a comprehensive investigation involving 360 adult MMD patients, finding that elevated serum glutamine levels were linked to increased stroke risk. Manipulation of integrin subunit beta 4 (ITGB4) and the use of atorvastatin was reported to alleviate the glutamine-induced EndMT, offering potential new therapeutic approaches for MMD.

Despite the severe presentations in MMD, the pathophysiological mechanisms driving MMD remain incompletely understood. The risk of stroke—a common and severe complication of MMD, is a pivotal aspect in reducing the devastating circumstances caused by MMD.

"Our research aimed to explore the role of in determining stroke risk and identify ," said Peicong Ge, the senior researcher of the study.

This study involved an in-depth investigation involving a cohort of 360 adult MMD patients. The researchers found that high glutamine levels were positively correlated with an increased risk of stroke, revealing a greater probability of either hemorrhagic or as the glutamine concentration rose.

Using human brain microvascular endothelial cells (HBMECs) as a model that accurately replicated the cellular environment of the brain's microvessel, the research team explored the effects of glutamine on these cells. The treatment of HBMEC with glutamine led to notable increases in , migration, and EndMT, illuminating the direct impact of glutamine on endothelial cell behavior.

This provided insight into a potential mechanism by which elevated glutamine levels could lead to the vascular abnormalities observed in MMD.

Crucially, these effects were reversed when the cells were genetically modified to reduce the levels of the protein integrin subunit beta 4 (ITGB4). Further analysis revealed that ITGB4 plays a role in the MAPK-ERK-TGF-β/BMP , which is activated during EndMT.

By targeting Smad4, a protein component of this pathway, the researchers demonstrated that knocking down Smad4 could inhibit the EndMT process. These observations indicate that ITGB4 and the signaling pathway it influences could be promising targets for therapeutic intervention.

In addition to the novel findings related to ITGB4, the study further unveiled the therapeutic potential of atorvastatin, a medication commonly prescribed to lower cholesterol. In lab experiments, atorvastatin was shown to suppress EndMT in ITGB4-transfected HBMECs by inhibiting Smad1/5 phosphorylation and inducing Smad4 ubiquitination, indicating that atorvastatin might offer a new use in treating MMD.

Supporting their laboratory findings, researchers also examined from the superficial temporal arteries of MMD patients, confirming that ITGB4 protein levels were indeed upregulated in affected individuals.

"This validation in human tissue is crucial as it bridges the gap between in vitro findings and clinical relevance," Dong Zhang added.

Concluding the study, the researchers point to glutamine as an for hemorrhage or infarction in MMD and suggest that interventions targeting ITGB4 or applying atorvastatin could offer novel therapeutic approaches capable of reducing in MMD patients.

"Our findings present a profound opportunity to shift how we approach the treatment of MMD," stated Qiheng He, the first author of the study.

"Beyond potentially using atorvastatin to target specific pathways involved in MMD, one most important thing is that we first clearly reported the phenomenon of EndMT in the endothelium of patients with MMD, which is further related to , providing a new idea for subsequent research on complex mechanisms of MMD and in revolutionizing the care and treatment of patients."

More information: Qiheng He et al, High glutamine increases stroke risk by inducing the endothelial‐to‐mesenchymal transition in moyamoya disease, MedComm (2024). DOI: 10.1002/mco2.525

Provided by Sichuan International Medical Exchange and Promotion Association
Citation: Elevated glutamine triggers stroke risk in moyamoya disease via endothelial‐to‐mesenchymal transition, finds study (2024, April 18) retrieved 22 May 2024 from
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