Platelet-derived calpain cleaves the endothelial protease-activated receptor 1 to induce vascular inflammation in diabet
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ORIGINAL CONTRIBUTION
Platelet‑derived calpain cleaves the endothelial protease‑activated receptor 1 to induce vascular inflammation in diabetes Anastasia Kyselova1,2 · Amro Elgheznawy1 · Ilka Wittig2,3 · Juliana Heidler2,3 · Alexander W. Mann4 · Wolfram Ruf2,5,6 · Ingrid Fleming1,2 · Voahanginirina Randriamboavonjy1,2 Received: 29 July 2020 / Accepted: 11 November 2020 © The Author(s) 2020
Abstract 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 plateletderived microparticles from diabetic patients or from wild-type mice but not from C APN1−/− 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. Keywords Endothelial cells · Microparticles · Endothelial protein C receptor · ICAM-1 · Calpain
Introduction Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00395-020-00833-9) contains supplementary material, which is available to authorized users. * Voahanginirina Randriamboavonjy [email protected]‑frankfurt.de 1
Institute for Vascular Signalling, Centre for Molecular Medicine, Goethe University, Theodor‑Stern‑Kai 7, 60596 Frankfurt am Main, Germany
2
German Center for Cardiovascular Research (DZHK), Partner site Rhein‑Main, Frankfurt am Main, Germany
3
Functional Proteomics, SFB 815 Core Unit, Goethe University, Frankfurt am Main, Germany
4
Endokrinologikum Frankfurt, 60596 Frankfurt am Main, Germany
5
Center for Thrombosis and Hemostasis, University Medical Center, Mainz, Germany
6
Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA, USA
Diabetes mellitus is a major risk factor for the development of cardiovascular disease(s), and the morbidity and mortality associated with diabetes are frequently related to micro- and macro-vascular complications, characterized by accelerated atherothromb
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