TY  - JOUR
A1  - Kyselova, Anastasia
A1  - Elgheznawy, Amro
A1  - Wittig, Ilka
A1  - Heidler, Juliana
A1  - Mann, Alexander W.
A1  - Ruf, Wolfram
A1  - Fleming, Ingrid
A1  - Randriamboavonjy, Voahanginirina
T1  - Platelet-derived calpain cleaves the endothelial protease-activated receptor 1 to induce vascular inflammation in diabetes
T2  - Basic research in cardiology
N2  - 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.
KW  - Endothelial cells
KW  - Microparticles
KW  - Endothelial protein C receptor
KW  - ICAM-1
KW  - Calpain
Y1  - 2020
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/74660
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-746609
SN  - 1435-1803
N1  - 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).
VL  - 115
IS  - 6, art. 75
SP  - 1
EP  - 13
PB  - Steinkopff ; Springer
CY  - [Darmstadt u.a.] ; Heidelberg
ER  -