Aging-induced isoDGR-modified fibronectin activates monocytic and endothelial cells to promote atherosclerosis
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 ro...
| Main Authors: | , , , , , , , , , , , , , , , , , |
|---|---|
| Other Authors: | |
| Format: | Journal Article |
| Language: | English |
| Published: |
2022
|
| Subjects: | |
| Online Access: | https://hdl.handle.net/10356/159531 |
| _version_ | 1826116795946237952 |
|---|---|
| author | 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 |
| author2 | School of Biological Sciences |
| author_facet | School of Biological Sciences 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 |
| author_sort | Park, Jung Eun |
| collection | NTU |
| 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 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. |
| first_indexed | 2024-10-01T04:17:17Z |
| format | Journal Article |
| id | ntu-10356/159531 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T04:17:17Z |
| publishDate | 2022 |
| record_format | dspace |
| spelling | ntu-10356/1595312022-06-24T07:17:19Z Aging-induced isoDGR-modified fibronectin activates monocytic and endothelial cells to promote atherosclerosis 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 School of Biological Sciences Lee Kong Chian School of Medicine (LKCMedicine) Duke-NUS Medical School Tan Tock Seng Hospital National University Health System Science::Biological sciences Science::Medicine Atherosclerosis Vascular Inflammation 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. Ministry of Education (MOE) National Medical Research Council (NMRC) This work was in part supported by grants from the National Medical Research Council of Singapore (NMRC–OF–IRG-0003-2016) and Ministry of Education of Singapore (MOE2018-T1-001-078). 2022-06-24T07:17:18Z 2022-06-24T07:17:18Z 2021 Journal Article 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. https://dx.doi.org/10.1016/j.atherosclerosis.2021.03.020 0021-9150 https://hdl.handle.net/10356/159531 10.1016/j.atherosclerosis.2021.03.020 33831670 2-s2.0-85103728407 324 58 68 en NMRC-OF-IRG-0003-2016 MOE2018-T1-001-078 Atherosclerosis © 2021 Elsevier B.V. All rights reserved. |
| spellingShingle | Science::Biological sciences Science::Medicine Atherosclerosis Vascular Inflammation 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 Aging-induced isoDGR-modified fibronectin activates monocytic and endothelial cells to promote atherosclerosis |
| title | Aging-induced isoDGR-modified fibronectin activates monocytic and endothelial cells to promote atherosclerosis |
| title_full | Aging-induced isoDGR-modified fibronectin activates monocytic and endothelial cells to promote atherosclerosis |
| title_fullStr | Aging-induced isoDGR-modified fibronectin activates monocytic and endothelial cells to promote atherosclerosis |
| title_full_unstemmed | Aging-induced isoDGR-modified fibronectin activates monocytic and endothelial cells to promote atherosclerosis |
| title_short | Aging-induced isoDGR-modified fibronectin activates monocytic and endothelial cells to promote atherosclerosis |
| title_sort | aging induced isodgr modified fibronectin activates monocytic and endothelial cells to promote atherosclerosis |
| topic | Science::Biological sciences Science::Medicine Atherosclerosis Vascular Inflammation |
| url | https://hdl.handle.net/10356/159531 |
| work_keys_str_mv | AT parkjungeun aginginducedisodgrmodifiedfibronectinactivatesmonocyticandendothelialcellstopromoteatherosclerosis AT jebamercygnanasekaran aginginducedisodgrmodifiedfibronectinactivatesmonocyticandendothelialcellstopromoteatherosclerosis AT pazhanchamykalailingam aginginducedisodgrmodifiedfibronectinactivatesmonocyticandendothelialcellstopromoteatherosclerosis AT guoxue aginginducedisodgrmodifiedfibronectinactivatesmonocyticandendothelialcellstopromoteatherosclerosis AT ngansofongcam aginginducedisodgrmodifiedfibronectinactivatesmonocyticandendothelialcellstopromoteatherosclerosis AT lioukenchengkang aginginducedisodgrmodifiedfibronectinactivatesmonocyticandendothelialcellstopromoteatherosclerosis AT soelynneinsi aginginducedisodgrmodifiedfibronectinactivatesmonocyticandendothelialcellstopromoteatherosclerosis AT ngsersue aginginducedisodgrmodifiedfibronectinactivatesmonocyticandendothelialcellstopromoteatherosclerosis AT mengwei aginginducedisodgrmodifiedfibronectinactivatesmonocyticandendothelialcellstopromoteatherosclerosis AT limsuchi aginginducedisodgrmodifiedfibronectinactivatesmonocyticandendothelialcellstopromoteatherosclerosis AT leowmelvinkheeshing aginginducedisodgrmodifiedfibronectinactivatesmonocyticandendothelialcellstopromoteatherosclerosis AT richardsamark aginginducedisodgrmodifiedfibronectinactivatesmonocyticandendothelialcellstopromoteatherosclerosis AT penningtondanielj aginginducedisodgrmodifiedfibronectinactivatesmonocyticandendothelialcellstopromoteatherosclerosis AT dekleijndominiquepv aginginducedisodgrmodifiedfibronectinactivatesmonocyticandendothelialcellstopromoteatherosclerosis AT sorokinvitaly aginginducedisodgrmodifiedfibronectinactivatesmonocyticandendothelialcellstopromoteatherosclerosis AT hoheehwa aginginducedisodgrmodifiedfibronectinactivatesmonocyticandendothelialcellstopromoteatherosclerosis AT mccarthyneile aginginducedisodgrmodifiedfibronectinactivatesmonocyticandendothelialcellstopromoteatherosclerosis AT szesiukwan aginginducedisodgrmodifiedfibronectinactivatesmonocyticandendothelialcellstopromoteatherosclerosis |