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Title: Aging-induced isoDGR-modified fibronectin activates monocytic and endothelial cells to promote atherosclerosis
Authors: Park, Jung Eun
JebaMercy, Gnanasekaran
Pazhanchamy, Kalailingam
Guo, Xue
Ngan, SoFong Cam
Liou, Ken Cheng Kang
Soe, Lynn EinSi
Ng, Ser Sue
Meng, Wei
Lim, Su Chi
Leow, Melvin Khee-Shing
Richards, A. Mark
Pennington, Daniel J.
de Kleijn, Dominique P. V.
Sorokin, Vitaly
Ho, Hee Hwa
McCarthy, Neil E.
Sze, Siu Kwan
Keywords: Science::Biological sciences
Issue Date: 2021
Source: Park, J. E., JebaMercy, G., Pazhanchamy, K., Guo, X., Ngan, S. C., Liou, K. C. K., Soe, L. E., Ng, S. S., Meng, W., Lim, S. C., Leow, M. K., Richards, A. M., Pennington, D. J., de Kleijn, D. P. V., Sorokin, V., Ho, H. H., McCarthy, N. E. & Sze, S. K. (2021). Aging-induced isoDGR-modified fibronectin activates monocytic and endothelial cells to promote atherosclerosis. Atherosclerosis, 324, 58-68.
Project: NMRC-OF-IRG-0003-2016
Journal: Atherosclerosis
Abstract: 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 TNFα to drive additional recruitment of circulating leukocytes. IsoDGR-modified fibronectin also induced endothelial cell expression of integrin β1 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.
ISSN: 0021-9150
DOI: 10.1016/j.atherosclerosis.2021.03.020
Schools: School of Biological Sciences 
Lee Kong Chian School of Medicine (LKCMedicine) 
Organisations: Duke-NUS Medical School
Tan Tock Seng Hospital
National University Health System
Rights: © 2021 Elsevier B.V. All rights reserved.
Fulltext Permission: none
Fulltext Availability: No Fulltext
Appears in Collections:LKCMedicine Journal Articles
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