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Upregulated Cytoskeletal Proteins Promote Pathological Angiogenesis in Moyamoya Disease
Shihao He1,2,3, Junze Zhang1, Ziqi Liu1
1Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, China (S.H., J.Z., Z.L., Y.W., X.H., X.W., Z.Z., X.Y., Yahui Zhao, Yuanli Zhao, R.W.).
Background:
Moyamoya disease (MMD) is a rare progressive vascular disease that leads to intracranial internal carotid artery stenosis and eventual occlusion. However, its pathogenesis remains unclear. The purpose of this study is to explore the role of abnormally expressed proteins in the pathogenesis of MMD.
Methods:
Data-independent acquisition mass spectrometry identifies the differentially expressed proteins in MMD serum by detecting the serum from 60 patients with MMD and 20 health controls. The differentially expressed proteins were validated using enzyme linked immunosorbent assays. Immunofluorescence for superficial temporal artery and middle cerebral artery specimens was used to explore the morphological changes of vascular wall in MMD. In vitro experiments were used to explore the changes and mechanisms of differentially expressed proteins on endothelial cells.
Results:
Proteomic analysis showed that a total of 14 726 peptides and 1555 proteins were quantified by mass spectrometry data. FLNA (filamin A) and ZYX (zyxin) proteins were significantly higher in MMD serum compared with those in health controls (Log2FC >2.9 and >2.8, respectively). Immunofluorescence revealed an intimal hyperplasia in superficial temporal artery and middle cerebral artery specimens of MMD. FLNA and ZYX proteins increased the proportion of endothelial cells in S phase and promoted their proliferation, angiogenesis, and cytoskeleton enlargement. Mechanistic studies revealed that AKT (serine/threonine kinase)/GSK-3β (glycogen synthase kinase 3β)/β-catenin signaling pathway plays a major role in these FLNA- and ZYX-induced changes in endothelial cells.
Conclusions:
This study provides proteomic data on a large sample size of MMD. The differential expression of FLNA and ZYX in patient with MMD and following in vitro experiments suggest that these upregulated proteins are related to the pathology of cerebrovascular intimal hyperplasia in MMD and are involved in MMD pathogenesis, with diagnostic and therapeutic ramifications.
Insights
This study identifies elevated filamin A (FLNA) and zyxin (ZYX) proteins in Moyamoya disease (MMD) patients. These proteins contribute to cerebrovascular intimal hyperplasia and MMD pathogenesis.
Area of Science:
- Proteomics
- Vascular Biology
- Molecular Medicine
Background:
- Moyamoya disease (MMD) is a rare, progressive cerebrovascular disorder characterized by stenosis and occlusion of intracranial arteries.
- The underlying pathogenesis of MMD remains incompletely understood.
- Identifying key molecular players is crucial for understanding MMD development.
Purpose of the Study:
- To investigate the role of abnormally expressed proteins in the pathogenesis of Moyamoya disease.
- To identify potential protein biomarkers for MMD diagnosis and therapy.
Main Methods:
- Utilized data-independent acquisition mass spectrometry on serum from 60 MMD patients and 20 healthy controls.
- Validated differentially expressed proteins using enzyme-linked immunosorbent assays (ELISAs).
- Performed immunofluorescence on vascular specimens and in vitro endothelial cell experiments to elucidate mechanisms.
Main Results:
- Quantified 1555 proteins, identifying significantly elevated levels of filamin A (FLNA) and zyxin (ZYX) in MMD serum.
- Immunofluorescence confirmed intimal hyperplasia in MMD vascular samples.
- FLNA and ZYX promoted endothelial cell proliferation, angiogenesis, and cytoskeleton changes via the AKT/GSK-3β/β-catenin pathway.
Conclusions:
- This large-scale proteomic study highlights FLNA and ZYX as significantly upregulated in MMD.
- These proteins are implicated in the cerebrovascular intimal hyperplasia characteristic of MMD.
- Findings suggest FLNA and ZYX have diagnostic and therapeutic potential for Moyamoya disease.
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