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
Parent Title (English):Basic research in cardiology
Publisher:Steinkopff ; Springer
Place of publication:[Darmstadt u.a.] ; Heidelberg
Document Type:Article
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
Issue:6, art. 75
Article Number:75
Page Number:13
First Page:1
Last Page:13
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).
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Licence (German):License LogoCreative Commons - CC BY - Namensnennung 4.0 International