Glycoproteomic Analysis of the Aortic Extracellular Matrix in Marfan Patients.
Yin 殷晓科, Xiaoke
Fellows, Adam L
Koolbergen, David R
Zwinderman, Aeilko H
de Vries, Carlie JM
Mulder, Barbara JM
Reinhardt, Dieter P
de Waard, Vivian
Arteriosclerosis, thrombosis, and vascular biology
Lippincott Williams & Wilkins Ltd.
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Yin 殷晓科, X., Wanga, S., Fellows, A. L., Barallobre-Barreiro, J., Lu, R., Davaapil, H., Franken, R., et al. (2019). Glycoproteomic Analysis of the Aortic Extracellular Matrix in Marfan Patients.. Arteriosclerosis, thrombosis, and vascular biology, 39 (9), 1859-1873. https://doi.org/10.1161/atvbaha.118.312175
OBJECTIVE: Marfan syndrome (MFS) is caused by mutations in FBN1 (fibrillin-1), an extracellular matrix (ECM) component, which is modified post-translationally by glycosylation. This study aimed to characterize the glycoproteome of the aortic ECM from patients with MFS and relate it to aortopathy. Approach and Results: ECM extracts of aneurysmal ascending aortic tissue from patients with and without MFS were enriched for glycopeptides. Direct N-glycopeptide analysis by mass spectrometry identified 141 glycoforms from 47 glycosites within 35 glycoproteins in the human aortic ECM. Notably, MFAP4 (microfibril-associated glycoprotein 4) showed increased and more diverse N-glycosylation in patients with MFS compared with control patients. MFAP4 mRNA levels were markedly higher in MFS aortic tissue. MFAP4 protein levels were also increased at the predilection (convexity) site for ascending aorta aneurysm in bicuspid aortic valve patients, preceding aortic dilatation. In human aortic smooth muscle cells, MFAP4 mRNA expression was induced by TGF (transforming growth factor)-β1 whereas siRNA knockdown of MFAP4 decreased FBN1 but increased elastin expression. These ECM changes were accompanied by differential gene expression and protein abundance of proteases from ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) family and their proteoglycan substrates, respectively. Finally, high plasma MFAP4 concentrations in patients with MFS were associated with a lower thoracic descending aorta distensibility and greater incidence of type B aortic dissection during 68 months follow-up. CONCLUSIONS: Our glycoproteomics analysis revealed that MFAP4 glycosylation is enhanced, as well as its expression during the advanced, aneurysmal stages of MFS compared with control aneurysms from patients without MFS.
Aorta, Extracellular Matrix, Myocytes, Smooth Muscle, Humans, Marfan Syndrome, Aortic Aneurysm, Thoracic, Glycopeptides, Glycoproteins, Carrier Proteins, Extracellular Matrix Proteins, Proteomics, Glycosylation, Vascular Remodeling, Fibrillin-1
British Heart Foundation (RG/17/5/32936)
External DOI: https://doi.org/10.1161/atvbaha.118.312175
This record's URL: https://www.repository.cam.ac.uk/handle/1810/294949
Attribution 4.0 International
Licence URL: https://creativecommons.org/licenses/by/4.0/