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Spatial proteomics analysis of soft and stiff regions in human acute arterial thrombus.
Stroke 54, 1636-1644 (2023)
Publ. Version/Full Text
DOI
PMC
BACKGROUND: The soft regions of a thrombus tend to be more susceptible to r-tPA (recombinant tissue-type plasminogen activator)-mediated thrombolysis and are more easily removed by mechanical thrombectomy than the stiff counterpart. This study aimed to understand the molecular pathological differences between the soft and stiff regions of human arterial thrombus. METHODS: We developed a spatial proteomic workflow combining proteomics with laser-captured microdissection to analyze human arterial thrombi with Masson trichrome staining to identify stiff and soft regions from 2 independent cohorts of patients with acute myocardial or cerebral infarction. Dysregulated proteins in a C57BL6/J male mouse model of arterial thrombosis were identified by pathway enrichment and pairwise analyses from the common gene ontology enrichment and dysregulated proteins between carotid and coronary arterial thrombi, and validated by immunohistochemistry. RESULTS: Spatial proteomics of the coronary arterial thrombi collected from 7 patients with myocardial infarct revealed 7 common dysregulated proteins in 2 cohorts of patients, and upregulation of TGF-β1 (transforming growth factor β1) was the most prominent fibrosis-related protein. Inhibition of TGF-β1 resulted in delayed arterial thrombosis and accelerated blood flow restoration in mouse model. We further expanded the spatial proteomic workflow to the carotid artery thrombi collected from 11 patients with cerebral infarction. Pairwise proteomic analysis of stiff and soft regions between carotid and coronary arterial thrombi further revealed 5 common gene ontology clusters including features of platelet activation, and a common dysregulated protein COL1A1 (collagen type 1 alpha 1) that was reported to be influenced by TGF-β1. We also verified the expression in human and mice carotid arterial thrombi. CONCLUSIONS: This study demonstrates the spatially distinct composition of proteins in the stiff and soft regions of human arterial thrombi, and suggests that TGF-β1 is a key therapeutic target for promoting arterial thrombolysis.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Microdissection ; Myocardial Infarction ; Proteomics ; Thrombectomy ; Thrombosis; Stroke; Thromboemboli
ISSN (print) / ISBN
0039-2499
e-ISSN
1524-4628
Journal
Stroke
Quellenangaben
Volume: 54,
Issue: 6,
Pages: 1636-1644
Publisher
Lippincott Williams & Wilkins
Publishing Place
Two Commerce Sq, 2001 Market St, Philadelphia, Pa 19103 Usa
Non-patent literature
Publications
Reviewing status
Peer reviewed
Institute(s)
Institute for Tissue Engineering and Regenerative Medicine (ITERM)
Grants
Outstanding Innovative Talents Cultivation Funded Programs for Doctoral Students of Jinan University
Science and Technology Program of Guangzhou, China
Fundamental Research Funds for the Central Universities
Natural Science Foundation of Guangdong Province
Science and Technology Planning Project of Guangdong Province, China
National Natural Science Foundation of China
Science and Technology Program of Guangzhou, China
Fundamental Research Funds for the Central Universities
Natural Science Foundation of Guangdong Province
Science and Technology Planning Project of Guangdong Province, China
National Natural Science Foundation of China