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Calciprotein Particles Cause Endothelial Dysfunction under Flow
Calciprotein particles (CPPs), which increasingly arise in the circulation during the disorders of mineral homeostasis, represent a double-edged sword protecting the human organism from extraskeletal calcification but potentially causing endothelial dysfunction. Existing models, however, failed to d...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7699979/ https://www.ncbi.nlm.nih.gov/pubmed/33233811 http://dx.doi.org/10.3390/ijms21228802 |
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author | Shishkova, Daria Markova, Victoria Sinitsky, Maxim Tsepokina, Anna Velikanova, Elena Bogdanov, Leo Glushkova, Tatiana Kutikhin, Anton |
author_facet | Shishkova, Daria Markova, Victoria Sinitsky, Maxim Tsepokina, Anna Velikanova, Elena Bogdanov, Leo Glushkova, Tatiana Kutikhin, Anton |
author_sort | Shishkova, Daria |
collection | PubMed |
description | Calciprotein particles (CPPs), which increasingly arise in the circulation during the disorders of mineral homeostasis, represent a double-edged sword protecting the human organism from extraskeletal calcification but potentially causing endothelial dysfunction. Existing models, however, failed to demonstrate the detrimental action of CPPs on endothelial cells (ECs) under flow. Here, we applied a flow culture system, where human arterial ECs were co-incubated with CPPs for 4 h, and a normolipidemic and normotensive rat model (10 daily intravenous injections of CPPs) to simulate the scenario occurring in vivo in the absence of confounding cardiovascular risk factors. Pathogenic effects of CPPs were investigated by RT-qPCR and Western blotting profiling of the endothelial lysate. CPPs were internalised within 1 h of circulation, inducing adhesion of peripheral blood mononuclear cells to ECs. Molecular profiling revealed that CPPs stimulated the expression of pro-inflammatory cell adhesion molecules VCAM1 and ICAM1 and upregulated transcription factors of endothelial-to-mesenchymal transition (Snail, Slug and Twist1). Furthermore, exposure to CPPs reduced the production of atheroprotective transcription factors KLF2 and KLF4 and led to YAP1 hypophosphorylation, potentially disturbing the mechanisms responsible for the proper endothelial mechanotransduction. Taken together, our results suggest the ability of CPPs to initiate endothelial dysfunction at physiological flow conditions. |
format | Online Article Text |
id | pubmed-7699979 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-76999792020-11-29 Calciprotein Particles Cause Endothelial Dysfunction under Flow Shishkova, Daria Markova, Victoria Sinitsky, Maxim Tsepokina, Anna Velikanova, Elena Bogdanov, Leo Glushkova, Tatiana Kutikhin, Anton Int J Mol Sci Article Calciprotein particles (CPPs), which increasingly arise in the circulation during the disorders of mineral homeostasis, represent a double-edged sword protecting the human organism from extraskeletal calcification but potentially causing endothelial dysfunction. Existing models, however, failed to demonstrate the detrimental action of CPPs on endothelial cells (ECs) under flow. Here, we applied a flow culture system, where human arterial ECs were co-incubated with CPPs for 4 h, and a normolipidemic and normotensive rat model (10 daily intravenous injections of CPPs) to simulate the scenario occurring in vivo in the absence of confounding cardiovascular risk factors. Pathogenic effects of CPPs were investigated by RT-qPCR and Western blotting profiling of the endothelial lysate. CPPs were internalised within 1 h of circulation, inducing adhesion of peripheral blood mononuclear cells to ECs. Molecular profiling revealed that CPPs stimulated the expression of pro-inflammatory cell adhesion molecules VCAM1 and ICAM1 and upregulated transcription factors of endothelial-to-mesenchymal transition (Snail, Slug and Twist1). Furthermore, exposure to CPPs reduced the production of atheroprotective transcription factors KLF2 and KLF4 and led to YAP1 hypophosphorylation, potentially disturbing the mechanisms responsible for the proper endothelial mechanotransduction. Taken together, our results suggest the ability of CPPs to initiate endothelial dysfunction at physiological flow conditions. MDPI 2020-11-20 /pmc/articles/PMC7699979/ /pubmed/33233811 http://dx.doi.org/10.3390/ijms21228802 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Shishkova, Daria Markova, Victoria Sinitsky, Maxim Tsepokina, Anna Velikanova, Elena Bogdanov, Leo Glushkova, Tatiana Kutikhin, Anton Calciprotein Particles Cause Endothelial Dysfunction under Flow |
title | Calciprotein Particles Cause Endothelial Dysfunction under Flow |
title_full | Calciprotein Particles Cause Endothelial Dysfunction under Flow |
title_fullStr | Calciprotein Particles Cause Endothelial Dysfunction under Flow |
title_full_unstemmed | Calciprotein Particles Cause Endothelial Dysfunction under Flow |
title_short | Calciprotein Particles Cause Endothelial Dysfunction under Flow |
title_sort | calciprotein particles cause endothelial dysfunction under flow |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7699979/ https://www.ncbi.nlm.nih.gov/pubmed/33233811 http://dx.doi.org/10.3390/ijms21228802 |
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