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High glutamine increases stroke risk by inducing the endothelial-to-mesenchymal transition in moyamoya disease
Qiheng He1, Junsheng Li1, Chuming Tao1
1Department of Neurosurgery Beijing Tiantan Hospital, Capital Medical University Beijing China.
Abstract:
At present, there is limited research on the mechanisms underlying moyamoya disease (MMD). Herein, we aimed to determine the role of glutamine in MMD pathogenesis, and 360 adult patients were prospectively enrolled. Human brain microvascular endothelial cells (HBMECs) were subjected to Integrin Subunit Beta 4 (ITGB4) overexpression or knockdown and atorvastatin. We assessed factors associated with various signaling pathways in the context of the endothelial-to-mesenchymal transition (EndMT), and the expression level of related proteins was validated in the superficial temporal arteries of patients. We found glutamine levels were positively associated with a greater risk of stroke (OR = 1.599, p = 0.022). After treatment with glutamine, HBMECs exhibited enhanced proliferation, migration, and EndMT, all reversed by ITGB4 knockdown. In ITGB4-transfected HBMECs, the MAPK-ERK-TGF-β/BMP pathway was activated, with Smad4 knockdown reversing the EndMT. Furthermore, atorvastatin suppressed the EndMT by inhibiting Smad1/5 phosphorylation and promoting Smad4 ubiquitination in ITGB4-transfected HBMECs. We also found the protein level of ITGB4 was upregulated in the superficial temporal arteries of patients with MMD. In conclusion, our study suggests that glutamine may be an independent risk factor for hemorrhage or infarction in patients with MMD and targeting ITGB4 could potentially be therapeutic approaches for MMD.
Insights
High glutamine levels increase stroke risk in moyamoya disease (MMD). Targeting Integrin Subunit Beta 4 (ITGB4) may offer new MMD therapies by reducing endothelial-to-mesenchymal transition.
Area of Science:
- Neuroscience
- Vascular Biology
- Biochemistry
Background:
- Moyamoya disease (MMD) pathogenesis mechanisms remain poorly understood.
- Limited research exists on the role of specific metabolites, like glutamine, in MMD.
- Endothelial-to-mesenchymal transition (EndMT) is implicated in vascular remodeling diseases.
Purpose of the Study:
- To investigate the role of glutamine in moyamoya disease (MMD) pathogenesis.
- To explore the involvement of Integrin Subunit Beta 4 (ITGB4) in MMD-related endothelial dysfunction.
- To assess potential therapeutic targets for MMD.
Main Methods:
- Prospective enrollment of 360 adult moyamoya disease patients.
- In vitro studies using human brain microvascular endothelial cells (HBMECs) with ITGB4 manipulation and atorvastatin treatment.
- Analysis of signaling pathways (MAPK-ERK-TGF-β/BMP) and protein expression (Smad4, Smad1/5) related to EndMT.
- Validation of protein expression in patient superficial temporal artery samples.
Main Results:
- Glutamine levels were positively associated with increased stroke risk in MMD patients (OR=1.599, p=0.022).
- Glutamine promoted HBMEC proliferation, migration, and EndMT, effects reversed by ITGB4 knockdown.
- ITGB4 overexpression activated the MAPK-ERK-TGF-β/BMP pathway; Smad4 knockdown inhibited EndMT.
- Atorvastatin suppressed EndMT by modulating Smad1/5 phosphorylation and Smad4 ubiquitination.
- ITGB4 protein levels were elevated in MMD patient arteries.
Conclusions:
- Glutamine may serve as an independent risk factor for hemorrhage or infarction in moyamoya disease.
- Integrin Subunit Beta 4 (ITGB4) plays a crucial role in MMD pathogenesis via EndMT.
- Targeting ITGB4 presents a potential therapeutic strategy for moyamoya disease.
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