Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Shishkova, Daria, Markova, Victoria, Sinitsky, Maxim, Tsepokina, Anna, Velikanova, Elena, Bogdanov, Leo, Glushkova, Tatiana, Kutikhin, Anton
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
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
_version_ 1783616173464616960
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
work_keys_str_mv AT shishkovadaria calciproteinparticlescauseendothelialdysfunctionunderflow
AT markovavictoria calciproteinparticlescauseendothelialdysfunctionunderflow
AT sinitskymaxim calciproteinparticlescauseendothelialdysfunctionunderflow
AT tsepokinaanna calciproteinparticlescauseendothelialdysfunctionunderflow
AT velikanovaelena calciproteinparticlescauseendothelialdysfunctionunderflow
AT bogdanovleo calciproteinparticlescauseendothelialdysfunctionunderflow
AT glushkovatatiana calciproteinparticlescauseendothelialdysfunctionunderflow
AT kutikhinanton calciproteinparticlescauseendothelialdysfunctionunderflow