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...
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creator | Shishkova, Daria Markova, Victoria Sinitsky, Maxim Tsepokina, Anna Velikanova, Elena Bogdanov, Leo Glushkova, Tatiana Kutikhin, Anton |
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. |
doi_str_mv | 10.3390/ijms21228802 |
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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.</description><identifier>ISSN: 1422-0067</identifier><identifier>ISSN: 1661-6596</identifier><identifier>EISSN: 1422-0067</identifier><identifier>DOI: 10.3390/ijms21228802</identifier><identifier>PMID: 33233811</identifier><language>eng</language><publisher>Switzerland: MDPI AG</publisher><subject>Animals ; Blood circulation ; Calcification ; Calcifying Nanoparticles - adverse effects ; Calcium - chemistry ; Cardiovascular diseases ; Cell adhesion ; Cell adhesion & migration ; Cell adhesion molecules ; Cell culture ; Cells, Cultured ; Coronary vessels ; Cytokines ; Endothelial cells ; Endothelial Cells - pathology ; Gene expression ; Homeostasis ; Humans ; Inflammation ; Intercellular adhesion molecule 1 ; Intravenous administration ; Investigations ; KLF4 protein ; Krueppel-like factor ; Leukocytes (mononuclear) ; Male ; Mechanotransduction ; Mechanotransduction, Cellular ; Mesenchyme ; Peripheral blood mononuclear cells ; Rats ; Rats, Wistar ; Risk analysis ; Risk factors ; Smooth muscle ; Snail protein ; Stress, Mechanical ; Transcription factors ; Vascular Diseases - metabolism ; Veins & arteries ; Western blotting ; Yes-associated protein</subject><ispartof>International journal of molecular sciences, 2020-11, Vol.21 (22), p.8802</ispartof><rights>2020. This work is licensed under http://creativecommons.org/licenses/by/3.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2020 by the authors. 2020</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c379t-945fff878047530b633d759fc148637adfbf540403009aa010997d191ded47823</citedby><cites>FETCH-LOGICAL-c379t-945fff878047530b633d759fc148637adfbf540403009aa010997d191ded47823</cites><orcidid>0000-0002-5959-1699 ; 0000-0001-8679-4857</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7699979/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7699979/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,724,777,781,882,27905,27906,53772,53774</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33233811$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Shishkova, Daria</creatorcontrib><creatorcontrib>Markova, Victoria</creatorcontrib><creatorcontrib>Sinitsky, Maxim</creatorcontrib><creatorcontrib>Tsepokina, Anna</creatorcontrib><creatorcontrib>Velikanova, Elena</creatorcontrib><creatorcontrib>Bogdanov, Leo</creatorcontrib><creatorcontrib>Glushkova, Tatiana</creatorcontrib><creatorcontrib>Kutikhin, Anton</creatorcontrib><title>Calciprotein Particles Cause Endothelial Dysfunction under Flow</title><title>International journal of molecular sciences</title><addtitle>Int J Mol Sci</addtitle><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.</description><subject>Animals</subject><subject>Blood circulation</subject><subject>Calcification</subject><subject>Calcifying Nanoparticles - adverse effects</subject><subject>Calcium - chemistry</subject><subject>Cardiovascular diseases</subject><subject>Cell adhesion</subject><subject>Cell adhesion & migration</subject><subject>Cell adhesion molecules</subject><subject>Cell culture</subject><subject>Cells, Cultured</subject><subject>Coronary vessels</subject><subject>Cytokines</subject><subject>Endothelial cells</subject><subject>Endothelial Cells - pathology</subject><subject>Gene expression</subject><subject>Homeostasis</subject><subject>Humans</subject><subject>Inflammation</subject><subject>Intercellular adhesion molecule 1</subject><subject>Intravenous administration</subject><subject>Investigations</subject><subject>KLF4 protein</subject><subject>Krueppel-like factor</subject><subject>Leukocytes (mononuclear)</subject><subject>Male</subject><subject>Mechanotransduction</subject><subject>Mechanotransduction, Cellular</subject><subject>Mesenchyme</subject><subject>Peripheral blood mononuclear cells</subject><subject>Rats</subject><subject>Rats, Wistar</subject><subject>Risk analysis</subject><subject>Risk factors</subject><subject>Smooth muscle</subject><subject>Snail protein</subject><subject>Stress, Mechanical</subject><subject>Transcription factors</subject><subject>Vascular Diseases - 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adverse effects</topic><topic>Calcium - chemistry</topic><topic>Cardiovascular diseases</topic><topic>Cell adhesion</topic><topic>Cell adhesion & migration</topic><topic>Cell adhesion molecules</topic><topic>Cell culture</topic><topic>Cells, Cultured</topic><topic>Coronary vessels</topic><topic>Cytokines</topic><topic>Endothelial cells</topic><topic>Endothelial Cells - pathology</topic><topic>Gene expression</topic><topic>Homeostasis</topic><topic>Humans</topic><topic>Inflammation</topic><topic>Intercellular adhesion molecule 1</topic><topic>Intravenous administration</topic><topic>Investigations</topic><topic>KLF4 protein</topic><topic>Krueppel-like factor</topic><topic>Leukocytes (mononuclear)</topic><topic>Male</topic><topic>Mechanotransduction</topic><topic>Mechanotransduction, Cellular</topic><topic>Mesenchyme</topic><topic>Peripheral blood mononuclear cells</topic><topic>Rats</topic><topic>Rats, Wistar</topic><topic>Risk analysis</topic><topic>Risk factors</topic><topic>Smooth muscle</topic><topic>Snail protein</topic><topic>Stress, Mechanical</topic><topic>Transcription factors</topic><topic>Vascular Diseases - 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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.</abstract><cop>Switzerland</cop><pub>MDPI AG</pub><pmid>33233811</pmid><doi>10.3390/ijms21228802</doi><orcidid>https://orcid.org/0000-0002-5959-1699</orcidid><orcidid>https://orcid.org/0000-0001-8679-4857</orcidid><oa>free_for_read</oa></addata></record> |
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subjects | Animals Blood circulation Calcification Calcifying Nanoparticles - adverse effects Calcium - chemistry Cardiovascular diseases Cell adhesion Cell adhesion & migration Cell adhesion molecules Cell culture Cells, Cultured Coronary vessels Cytokines Endothelial cells Endothelial Cells - pathology Gene expression Homeostasis Humans Inflammation Intercellular adhesion molecule 1 Intravenous administration Investigations KLF4 protein Krueppel-like factor Leukocytes (mononuclear) Male Mechanotransduction Mechanotransduction, Cellular Mesenchyme Peripheral blood mononuclear cells Rats Rats, Wistar Risk analysis Risk factors Smooth muscle Snail protein Stress, Mechanical Transcription factors Vascular Diseases - metabolism Veins & arteries Western blotting Yes-associated protein |
title | Calciprotein Particles Cause Endothelial Dysfunction under Flow |
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