期刊
EUROPEAN HEART JOURNAL
卷 32, 期 6, 页码 760-771出版社
OXFORD UNIV PRESS
DOI: 10.1093/eurheartj/ehq206
关键词
Atherosclerosis; Endothelial dysfunction; Plasma biomarkers; Endothelial microparticles; T-cadherin
资金
- Swiss National Science Foundation [310000-118468/1]
- Kamillo Eisner Stiftung
- Schweizerische HerzStiftung
- Herzkreislauf Stiftung
- Astra Zeneca
- Novartis Foundation for Medical Biological Research
Aims The presence of endothelial cell (EC)-derived surface molecules in the circulation is among hallmarks of endothelial activation and damage in vivo. Previous investigations suggest that upregulation of T-cadherin (T-cad) on the surface of ECs may be a characteristic marker of EC activation and stress. We investigated whether T-cad might also be shed from ECs and in amounts reflecting the extent of activation or damage. Methods and results Immunoblotting showed the presence of T-cad protein in the culture medium from normal proliferating ECs and higher levels in the medium from stressed/apoptotic ECs. Release of T-cad into the circulation occurs in vivo and in association with endothelial dysfunction. Sandwich ELISA revealed negligible T-cad protein in the plasma of healthy volunteers (0.90 +/- 0.90 ng/mL, n = 30), and increased levels in the plasma from patients with non-significant atherosclerosis (9.23 +/- 2.61 ng/mL, n = 63) and patients with chronic coronary artery disease (6.93 +/- 1.31 ng/mL, n = 162). In both patient groups there was a significant (P = 0.043) dependency of T-cad and degree of endothelial dysfunction as measured by reactive hyperaemia peripheral tonometry. Flow cytometry analysis showed that the major fraction of T-cad was released into the EC culture medium and the plasma as a surface component of EC-derived annexin V-and CD144/CD31-positive microparticles (MPs). Gain-of-function and loss-of-function studies demonstrate that MP-bound T-cad induced Akt phosphorylation and activated angiogenic behaviour in target ECs via homophilic-based interactions. Conclusion Our findings reveal a novel mechanism of T-cad-dependent signalling in the vascular endothelium. We identify T-cad as an endothelial MP antigen in vivo and demonstrate that its level in plasma is increased in early atherosclerosis and correlates with endothelial dysfunction.
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