Extracellular Matrix Proteomics Reveals Interplay of Aggrecan and Aggrecanases in Vascular Remodeling of Stented Coronary Arteries.

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  • Additional Information
    • Source:
      Publisher: Lippincott Williams & Wilkins Country of Publication: United States NLM ID: 0147763 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1524-4539 (Electronic) Linking ISSN: 00097322 NLM ISO Abbreviation: Circulation Subsets: MEDLINE
    • Publication Information:
      Publication: Hagerstown, MD : Lippincott Williams & Wilkins
      Original Publication: [Dallas, Tex., etc., American Heart Association, etc.]
    • Subject Terms:
      Aggrecans* ; Stents* ; Vascular Remodeling*; ADAMTS Proteins/*metabolism ; Coronary Vessels/*surgery ; Endopeptidases/*metabolism ; Extracellular Matrix/*enzymology ; Percutaneous Coronary Intervention/*instrumentation ; Proteomics/*methods; ADAMTS Proteins/genetics ; ADAMTS5 Protein/genetics ; ADAMTS5 Protein/metabolism ; Animals ; Chromatography, High Pressure Liquid ; Coronary Vessels/enzymology ; Coronary Vessels/physiopathology ; Drug-Eluting Stents ; Endopeptidases/genetics ; Female ; Humans ; Male ; Metals ; Mice, Knockout ; Models, Animal ; Neointima ; Prosthesis Design ; Signal Transduction ; Sus scrofa ; Tandem Mass Spectrometry ; Time Factors
    • Abstract:
      Background: Extracellular matrix (ECM) remodeling contributes to in-stent restenosis and thrombosis. Despite its important clinical implications, little is known about ECM changes post-stent implantation.
      Methods: Bare-metal and drug-eluting stents were implanted in pig coronary arteries with an overstretch under optical coherence tomography guidance. Stented segments were harvested 1, 3, 7, 14, and 28 days post-stenting for proteomics analysis of the media and neointima.
      Results: A total of 151 ECM and ECM-associated proteins were identified by mass spectrometry. After stent implantation, proteins involved in regulating calcification were upregulated in the neointima of drug-eluting stents. The earliest changes in the media were proteins involved in inflammation and thrombosis, followed by changes in regulatory ECM proteins. By day 28, basement membrane proteins were reduced in drug-eluting stents in comparison with bare-metal stents. In contrast, the large aggregating proteoglycan aggrecan was increased. Aggrecanases of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) family contribute to the catabolism of vascular proteoglycans. An increase in ADAMTS-specific aggrecan fragments was accompanied by a notable shift from ADAMTS1 and ADAMTS5 to ADAMTS4 gene expression after stent implantation. Immunostaining in human stented coronary arteries confirmed the presence of aggrecan and aggrecan fragments, in particular, at the contacts of the stent struts with the artery. Further investigation of aggrecan presence in the human vasculature revealed that aggrecan and aggrecan cleavage were more abundant in human arteries than in human veins. In addition, aggrecan synthesis was induced on grafting a vein into the arterial circulation, suggesting an important role for aggrecan in vascular plasticity. Finally, lack of ADAMTS-5 activity in mice resulted in an accumulation of aggrecan and a dilation of the thoracic aorta, confirming that aggrecanase activity regulates aggrecan abundance in the arterial wall and contributes to vascular remodeling.
      Conclusions: Significant differences were identified by proteomics in the ECM of coronary arteries after bare-metal and drug-eluting stent implantation, most notably an upregulation of aggrecan, a major ECM component of cartilaginous tissues that confers resistance to compression. The accumulation of aggrecan coincided with a shift in ADAMTS gene expression. This study provides the first evidence implicating aggrecan and aggrecanases in the vascular injury response after stenting.
      (© 2017 The Authors.)
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    • Grant Information:
      PG/17/48/32956 United Kingdom BHF_ British Heart Foundation; RG/16/14/32397 United Kingdom BHF_ British Heart Foundation; FS/13/2/29892 United Kingdom BHF_ British Heart Foundation; RG/11/14/29056 United Kingdom BHF_ British Heart Foundation; CH/16/3/32406 United Kingdom BHF_ British Heart Foundation; RG/17/2/32808 United Kingdom BHF_ British Heart Foundation
    • Contributed Indexing:
      Keywords: coronary artery; disease; extracellular matrix; mass spectrometry; neointima; stents
    • Accession Number:
      0 (Aggrecans)
      0 (Metals)
      EC 3.4.- (Endopeptidases)
      EC 3.4.24.- (ADAMTS Proteins)
      EC 3.4.24.- (ADAMTS5 Protein)
      EC 3.4.24.- (Adamts5 protein, mouse)
      EC 3.4.99.- (aggrecanase)
    • Publication Date:
      Date Created: 20171015 Date Completed: 20190401 Latest Revision: 20210109
    • Publication Date:
      20250114
    • Accession Number:
      PMC5757669
    • Accession Number:
      10.1161/CIRCULATIONAHA.116.023381
    • Accession Number:
      29030347