Platelet-derived calpain cleaves the endothelial protease-activated receptor 1 to induce vascular inflammation in diabetes
| العنوان: | Platelet-derived calpain cleaves the endothelial protease-activated receptor 1 to induce vascular inflammation in diabetes |
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| المؤلفون: | Ilka Wittig, Amro Elgheznawy, Anastasia Kyselova, Ingrid Fleming, Juliana Heidler, Wolfram Ruf, Alexander W. Mann, Voahanginirina Randriamboavonjy |
| المصدر: | Basic Research in Cardiology |
| بيانات النشر: | Springer Science and Business Media LLC, 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | Adult, Blood Platelets, Male, Vasculitis, 0301 basic medicine, Proteases, ICAM-1, Physiology, Endothelial cells, Microparticles, ADAM17 Protein, 030204 cardiovascular system & hematology, Pharmacology, Endothelial protein C receptor, Diabetes Mellitus, Experimental, 03 medical and health sciences, 0302 clinical medicine, Cell-Derived Microparticles, Physiology (medical), Animals, Humans, Receptor, PAR-1, Receptor, Cells, Cultured, Mice, Knockout, biology, Calpain, Tumor Necrosis Factor-alpha, Chemistry, Original Contribution, Middle Aged, Intercellular Adhesion Molecule-1, Mice, Inbred C57BL, Endothelial stem cell, 030104 developmental biology, Protease-Activated Receptor 1, Diabetes Mellitus, Type 2, Case-Control Studies, biology.protein, Female, Tumor necrosis factor alpha, Cardiology and Cardiovascular Medicine, Diabetic Angiopathies |
| الوصف: | 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. Electronic supplementary material The online version of this article (10.1007/s00395-020-00833-9) contains supplementary material, which is available to authorized users. |
| تدمد: | 1435-1803 0300-8428 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::2db0fd4af34ef2237db3a62e2ab2627cTest https://doi.org/10.1007/s00395-020-00833-9Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....2db0fd4af34ef2237db3a62e2ab2627c |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14351803 03008428 |
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