PXD024380-1

PXD024380 is an original dataset announced via ProteomeXchange.

Title	Aging-induced isoDGR-modified fibronectin activates monocytic and endothelial cells to promote atherosclerosis
Description	Background and Aims Aging is the primary risk factor for cardiovascular disease (CVD), but the mechanisms underlying age-linked atherosclerosis remain unclear. We previously observed that long-lived vascular matrix proteins can acquire ‘gain-of-function’ isoDGR motifs that might play a role in atherosclerotic pathology. Methods: IsoDGR-specific mAb were generated and used for ELISA-based measurement of motif levels in plasma samples from patients with coronary artery diseases (CAD) and non-CAD controls. Functional consequences of isoDGR accumulation in age-damaged fibronectin were determined by bioassay for capacity to activate monocytes, macrophages, and endothelial cells (signalling activity, pro-inflammatory cytokine expression, and recruitment/adhesion potential). Mice deficient in the isoDGR repair enzyme PCMT1 were used to assess motif distribution and macrophage localisation in vivo. Results: IsoDGR-modified fibronectin and fibrinogen levels in patient plasma were significantly enhanced in CAD and further associated with smoking status. Functional assays demonstrated that isoDGR-modified fibronectin activated both monocytes and macrophages via integrin receptor ‘outside in’ signalling, triggering an ERK:AP-1 cascade and expression of pro-inflammatory cytokines MCP-1 and TNF to drive additional recruitment of circulating leukocytes. IsoDGR-modified fibronectin also induced endothelial cell expression of integrin 1 to further enhance cellular adhesion and matrix deposition. Analysis of murine aortic tissues confirmed accumulation of isoDGR-modified proteins co-localised with CD68+ macrophages in vivo. Conclusions: Age-damaged fibronectin features isoDGR motifs that increase binding to integrins on the surface of monocytes, macrophages, and endothelial cells. Subsequent activation of ‘outside-in’ signalling elicits a range of potent cytokines and chemokines that drive additional leukocyte recruitment to the developing atherosclerotic matrix.
HostingRepository	PRIDE
AnnounceDate	2022-10-25
AnnouncementXML	Submission_2022-10-25_09:19:02.321.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	SoFong CamNgan
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	monohydroxylated residue; deamidated residue; iodoacetamide derivatized residue
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2021-02-25 02:57:48	ID requested
⏵ 1	2022-10-25 09:19:05	announced
2	2023-11-14 07:42:38	announced	2023-11-14: Updated project metadata.

submitter keyword: vascular inflammation,Atherosclerosis, isoDGR motif, fibronectin, integrin, deamidation

newmansze
contact affiliation	Nanyang Technological University
contact email	sksze@ntu.edu.sg
lab head
SoFong CamNgan
contact affiliation	Nanyang Technological University
contact email	sfcngan@ntu.edu.sg
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD024380
     1. Label: PRIDE project
     2. Name: Aging-induced isoDGR-modified fibronectin activates monocytic and endothelial cells to promote atherosclerosis