Platelet-derived calpain cleaves the endothelial protease-activated receptor 1 to induce vascular inflammation in diabetes
- Diabetes mellitus is a major risk factor for cardiovascular disease. Platelets from diabetic patients are hyperreactive and release microparticles that carry activated cysteine proteases or calpains. Whether platelet-derived calpains contribute to the development of vascular complications in diabetes is unknown. Here we report that platelet-derived calpain1 (CAPN1) cleaves the protease-activated receptor 1 (PAR-1) on the surface of endothelial cells, which then initiates a signaling cascade that includes the activation of the tumor necrosis factor (TNF)-α converting enzyme (TACE). The latter elicits the shedding of the endothelial protein C receptor and the generation of TNF-α, which in turn, induces intracellular adhesion molecule (ICAM)-1 expression to promote monocyte adhesion. All of the effects of CAPN1 were mimicked by platelet-derived microparticles from diabetic patients or from wild-type mice but not from CAPN1−/− mice, and were not observed in PAR-1-deficient endothelial cells. Importantly, aortae from diabetic mice expressed less PAR-1 but more ICAM-1 than non-diabetic mice, effects that were prevented by treating diabetic mice with a calpain inhibitor as well as by the platelet specific deletion of CAPN1. Thus, platelet-derived CAPN1 contributes to the initiation of the sterile vascular inflammation associated with diabetes via the cleavage of PAR-1 and the release of TNF-α from the endothelial cell surface.
Author: | Anastasia KyselovaGND, Amro ElgheznawyGND, Ilka WittigORCiD, Juliana HeidlerORCiD, Alexander W. Mann, Wolfram RufORCiD, Ingrid FlemingORCiDGND, Voahanginirina RandriamboavonjyORCiDGND |
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URN: | urn:nbn:de:hebis:30:3-746609 |
DOI: | https://doi.org/10.1007/s00395-020-00833-9 |
ISSN: | 1435-1803 |
Parent Title (English): | Basic research in cardiology |
Publisher: | Steinkopff ; Springer |
Place of publication: | [Darmstadt u.a.] ; Heidelberg |
Document Type: | Article |
Language: | English |
Date of Publication (online): | 2020/12/01 |
Date of first Publication: | 2020/12/01 |
Publishing Institution: | Universitätsbibliothek Johann Christian Senckenberg |
Release Date: | 2023/08/03 |
Tag: | Calpain; Endothelial cells; Endothelial protein C receptor; ICAM-1; Microparticles |
Volume: | 115 |
Issue: | 6, art. 75 |
Article Number: | 75 |
Page Number: | 13 |
First Page: | 1 |
Last Page: | 13 |
Note: | Open Access funding enabled and organized by Projekt DEAL. This work was supported by the Deutsche Forschungsgemeinschaft (RA 2435/3-1 to VR, SFB 815/A16 to IF, SFB 815/Z1 to IW and Excellence Cluster Cardio-Pulmonary Institute, EXC 2026, Project ID: 390649896). |
HeBIS-PPN: | 511285329 |
Institutes: | Medizin |
Dewey Decimal Classification: | 6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit |
Sammlungen: | Universitätspublikationen |
Licence (German): | Creative Commons - CC BY - Namensnennung 4.0 International |