Aging-induced isoDGR-modified fibronectin activates monocytic and endothelial cells to promote atherosclerosis
| Autor: | Ser Sue Ng, SoFong Cam Ngan, Gnanasekaran JebaMercy, Wei Meng, Xue Guo, Jung Eun Park, Dominique de Kleijn, Kalailingam Pazhanchamy, Siu Kwan Sze, Vitaly Sorokin, Daniel J. Pennington, A. Mark Richards, Ken Cheng Kang Liou, Neil E. McCarthy, Hee Hwa Ho, Melvin Khee-Shing Leow, Soe EinSi Lynn, Su Chi Lim |
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| Přispěvatelé: | School of Biological Sciences, Lee Kong Chian School of Medicine (LKCMedicine), Duke-NUS Medical School, Tan Tock Seng Hospital, National University Health System |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Aging Chemokine Integrin 030204 cardiovascular system & hematology Monocytes Mice 03 medical and health sciences 0302 clinical medicine Protein D-Aspartate-L-Isoaspartate Methyltransferase Cell Adhesion Animals Humans Macrophage Medicine [Science] Cell adhesion biology Chemistry CD68 Biological sciences [Science] Endothelial Cells Vascular Inflammation Atherosclerosis Fibronectins Cell biology Endothelial stem cell Fibronectin 030104 developmental biology biology.protein Tumor necrosis factor alpha Cardiology and Cardiovascular Medicine |
| Zdroj: | Atherosclerosis. 324:58-68 |
| ISSN: | 0021-9150 |
| Popis: | 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). |
| Databáze: | OpenAIRE |
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