PXD024380

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	2023-11-14
AnnouncementXML	Submission_2023-11-14_07:42:35.132.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	SoFong Cam Ngan
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.

Park JE, JebaMercy G, Pazhanchamy K, Guo X, Ngan SC, Liou KCK, Lynn SE, Ng SS, Meng W, Lim SC, Leow MK, Richards AM, Pennington DJ, de Kleijn DPV, Sorokin V, Ho HH, McCarthy NE, Sze SK, Aging-induced isoDGR-modified fibronectin activates monocytic and endothelial cells to promote atherosclerosis. Atherosclerosis, 324():58-68(2021) [pubmed]

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

newman sze
contact affiliation	Nanyang Technological University
contact email	sksze@ntu.edu.sg
lab head
SoFong Cam Ngan
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