The Metabolism of Epoxyeicosatrienoic Acids by Soluble Epoxide Hydrolase Is Protective against the Development of Vascular Calcification
This study addressed the hypothesis that soluble epoxide hydrolase (sEH), which metabolizes endothelium-derived epoxyeicosatrienoic acids, plays a role in vascular calcification. The sEH inhibitor -4-(4-(3-adamantan-1-yl-ureido)-cyclohexyloxy)-benzoic acid ( -AUCB) potentiated the increase in calciu...
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| Veröffentlicht in: | International journal of molecular sciences 2020-06, Vol.21 (12), p.4313 |
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| creator | Varennes, Olivier Mentaverri, Romuald Duflot, Thomas Kauffenstein, Gilles Objois, Thibaut Lenglet, Gaëlle Avondo, Carine Morisseau, Christophe Brazier, Michel Kamel, Saïd Six, Isabelle Bellien, Jeremy |
| description | This study addressed the hypothesis that soluble epoxide hydrolase (sEH), which metabolizes endothelium-derived epoxyeicosatrienoic acids, plays a role in vascular calcification. The sEH inhibitor
-4-(4-(3-adamantan-1-yl-ureido)-cyclohexyloxy)-benzoic acid (
-AUCB) potentiated the increase in calcium deposition of rat aortic rings cultured in high-phosphate conditions. This was associated with increased tissue-nonspecific alkaline phosphatase activity and mRNA expression level of the osteochondrogenic marker Runx2. The procalcifying effect of
-AUCB was prevented by mechanical aortic deendothelialization or inhibition of the production and action of epoxyeicosatrienoic acids using the cytochrome P450 inhibitor fluconazole and the antagonist 14,15-epoxyeicosa-5(Z)-enoic acid (14,15-EEZE), respectively. Similarly, exogenous epoxyeicosatrienoic acids potentiated the calcification of rat aortic rings through a protein kinase A (PKA)-dependent mechanism and of human aortic vascular smooth muscle cells when sEH was inhibited by
-AUCB. Finally, a global gene expression profiling analysis revealed that the mRNA expression level of sEH was decreased in human carotid calcified plaques compared to adjacent lesion-free sites and was inversely correlated with Runx2 expression. These results show that sEH hydrolase plays a protective role against vascular calcification by reducing the bioavailability of epoxyeicosatrienoic acids. |
| doi_str_mv | 10.3390/ijms21124313 |
| format | Article |
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-4-(4-(3-adamantan-1-yl-ureido)-cyclohexyloxy)-benzoic acid (
-AUCB) potentiated the increase in calcium deposition of rat aortic rings cultured in high-phosphate conditions. This was associated with increased tissue-nonspecific alkaline phosphatase activity and mRNA expression level of the osteochondrogenic marker Runx2. The procalcifying effect of
-AUCB was prevented by mechanical aortic deendothelialization or inhibition of the production and action of epoxyeicosatrienoic acids using the cytochrome P450 inhibitor fluconazole and the antagonist 14,15-epoxyeicosa-5(Z)-enoic acid (14,15-EEZE), respectively. Similarly, exogenous epoxyeicosatrienoic acids potentiated the calcification of rat aortic rings through a protein kinase A (PKA)-dependent mechanism and of human aortic vascular smooth muscle cells when sEH was inhibited by
-AUCB. Finally, a global gene expression profiling analysis revealed that the mRNA expression level of sEH was decreased in human carotid calcified plaques compared to adjacent lesion-free sites and was inversely correlated with Runx2 expression. These results show that sEH hydrolase plays a protective role against vascular calcification by reducing the bioavailability of epoxyeicosatrienoic acids.</description><identifier>ISSN: 1422-0067</identifier><identifier>ISSN: 1661-6596</identifier><identifier>EISSN: 1422-0067</identifier><identifier>DOI: 10.3390/ijms21124313</identifier><identifier>PMID: 32560362</identifier><language>eng</language><publisher>Switzerland: MDPI AG</publisher><subject>Alkaline phosphatase ; Animals ; Aorta ; Benzoic acid ; Bioavailability ; Biomedical materials ; Calcification ; Calcification (ectopic) ; Calcium ; Carotid Arteries - metabolism ; Carotid Arteries - pathology ; Cbfa-1 protein ; Cell Differentiation ; Cytochrome ; Cytochrome P450 ; Cytochromes P450 ; Disease Susceptibility ; Endothelium ; Endothelium - metabolism ; Epoxide hydrolase ; Epoxide Hydrolases - metabolism ; Experiments ; Fatty Acids, Monounsaturated - metabolism ; Fluconazole ; Gene expression ; Humans ; Kinases ; Life Sciences ; Lipid Metabolism ; Metabolism ; Metabolites ; Mineralization ; Muscles ; Phosphatase ; Phosphoric Monoester Hydrolases - metabolism ; Plaques ; Protein kinase A ; Rats ; RNA, Messenger - genetics ; Smooth muscle ; Staphylococcal enterotoxin H ; Vascular Calcification - etiology ; Vascular Calcification - metabolism</subject><ispartof>International journal of molecular sciences, 2020-06, Vol.21 (12), p.4313</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>Distributed under a Creative Commons Attribution 4.0 International License</rights><rights>2020 by the authors. 2020</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c446t-742cb9102e8cc58be2a121d7c41d7bd3a0f3e4bcdba9875d44055d6e0c4f07ed3</citedby><cites>FETCH-LOGICAL-c446t-742cb9102e8cc58be2a121d7c41d7bd3a0f3e4bcdba9875d44055d6e0c4f07ed3</cites><orcidid>0000-0002-8730-284X ; 0000-0003-0827-4746 ; 0000-0002-0383-2342 ; 0000-0003-0572-844X ; 0000-0002-3993-1561 ; 0000-0002-5256-8138 ; 0000-0001-9310-7840</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/PMC7352784/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352784/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32560362$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://u-picardie.hal.science/hal-03346167$$DView record in HAL$$Hfree_for_read</backlink></links><search><creatorcontrib>Varennes, Olivier</creatorcontrib><creatorcontrib>Mentaverri, Romuald</creatorcontrib><creatorcontrib>Duflot, Thomas</creatorcontrib><creatorcontrib>Kauffenstein, Gilles</creatorcontrib><creatorcontrib>Objois, Thibaut</creatorcontrib><creatorcontrib>Lenglet, Gaëlle</creatorcontrib><creatorcontrib>Avondo, Carine</creatorcontrib><creatorcontrib>Morisseau, Christophe</creatorcontrib><creatorcontrib>Brazier, Michel</creatorcontrib><creatorcontrib>Kamel, Saïd</creatorcontrib><creatorcontrib>Six, Isabelle</creatorcontrib><creatorcontrib>Bellien, Jeremy</creatorcontrib><title>The Metabolism of Epoxyeicosatrienoic Acids by Soluble Epoxide Hydrolase Is Protective against the Development of Vascular Calcification</title><title>International journal of molecular sciences</title><addtitle>Int J Mol Sci</addtitle><description>This study addressed the hypothesis that soluble epoxide hydrolase (sEH), which metabolizes endothelium-derived epoxyeicosatrienoic acids, plays a role in vascular calcification. The sEH inhibitor
-4-(4-(3-adamantan-1-yl-ureido)-cyclohexyloxy)-benzoic acid (
-AUCB) potentiated the increase in calcium deposition of rat aortic rings cultured in high-phosphate conditions. This was associated with increased tissue-nonspecific alkaline phosphatase activity and mRNA expression level of the osteochondrogenic marker Runx2. The procalcifying effect of
-AUCB was prevented by mechanical aortic deendothelialization or inhibition of the production and action of epoxyeicosatrienoic acids using the cytochrome P450 inhibitor fluconazole and the antagonist 14,15-epoxyeicosa-5(Z)-enoic acid (14,15-EEZE), respectively. Similarly, exogenous epoxyeicosatrienoic acids potentiated the calcification of rat aortic rings through a protein kinase A (PKA)-dependent mechanism and of human aortic vascular smooth muscle cells when sEH was inhibited by
-AUCB. Finally, a global gene expression profiling analysis revealed that the mRNA expression level of sEH was decreased in human carotid calcified plaques compared to adjacent lesion-free sites and was inversely correlated with Runx2 expression. These results show that sEH hydrolase plays a protective role against vascular calcification by reducing the bioavailability of epoxyeicosatrienoic acids.</description><subject>Alkaline phosphatase</subject><subject>Animals</subject><subject>Aorta</subject><subject>Benzoic acid</subject><subject>Bioavailability</subject><subject>Biomedical materials</subject><subject>Calcification</subject><subject>Calcification (ectopic)</subject><subject>Calcium</subject><subject>Carotid Arteries - metabolism</subject><subject>Carotid Arteries - pathology</subject><subject>Cbfa-1 protein</subject><subject>Cell Differentiation</subject><subject>Cytochrome</subject><subject>Cytochrome P450</subject><subject>Cytochromes P450</subject><subject>Disease Susceptibility</subject><subject>Endothelium</subject><subject>Endothelium - metabolism</subject><subject>Epoxide hydrolase</subject><subject>Epoxide Hydrolases - metabolism</subject><subject>Experiments</subject><subject>Fatty Acids, Monounsaturated - metabolism</subject><subject>Fluconazole</subject><subject>Gene expression</subject><subject>Humans</subject><subject>Kinases</subject><subject>Life Sciences</subject><subject>Lipid Metabolism</subject><subject>Metabolism</subject><subject>Metabolites</subject><subject>Mineralization</subject><subject>Muscles</subject><subject>Phosphatase</subject><subject>Phosphoric Monoester Hydrolases - metabolism</subject><subject>Plaques</subject><subject>Protein kinase A</subject><subject>Rats</subject><subject>RNA, Messenger - genetics</subject><subject>Smooth muscle</subject><subject>Staphylococcal enterotoxin H</subject><subject>Vascular Calcification - etiology</subject><subject>Vascular Calcification - metabolism</subject><issn>1422-0067</issn><issn>1661-6596</issn><issn>1422-0067</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>BENPR</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNpdkktvEzEQgFcIRF_cOCNLXKhEwM99XJCiUEilICpRuFp-zDaOvOvU9kbkH_Cz2TRtlfbisezP34ztKYq3BH9irMGf3apLlBDKGWEvimPCKZ1gXFYvD-ZHxUlKK4wpo6J5XRyNocSspMfFv-sloB-QlQ7epQ6FFl2sw98tOBOSytFBH5xBU-NsQnqLfgU_aA93kLOA5lsbg1cJ0GVCVzFkMNltAKkb5fqUUR71X2EDPqw76PPO_0clM3gV0Ux541pnVHahPytetconeHMfT4vf3y6uZ_PJ4uf3y9l0MTGcl3lScWp0QzCF2hhRa6CKUGIrw8dBW6Zwy4BrY7Vq6kpYzrEQtgRseIsrsOy0-LL3rgfdgTVjUVF5uY6uU3Erg3Ly6U7vlvImbGTFBK1qPgrO94Lls2Pz6ULu1jBjvCRltSEj--E-WQy3A6QsO5cMeK96CEOSlBNBm2avff8MXYUh9uNT3FGiLJtajNTHPWViSClC-1gBwXLXDvKwHUb83eFlH-GH_2f_AZ1Gsz0</recordid><startdate>20200617</startdate><enddate>20200617</enddate><creator>Varennes, Olivier</creator><creator>Mentaverri, Romuald</creator><creator>Duflot, Thomas</creator><creator>Kauffenstein, Gilles</creator><creator>Objois, Thibaut</creator><creator>Lenglet, Gaëlle</creator><creator>Avondo, Carine</creator><creator>Morisseau, Christophe</creator><creator>Brazier, Michel</creator><creator>Kamel, Saïd</creator><creator>Six, Isabelle</creator><creator>Bellien, Jeremy</creator><general>MDPI AG</general><general>MDPI</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>M2O</scope><scope>MBDVC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>7X8</scope><scope>1XC</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-8730-284X</orcidid><orcidid>https://orcid.org/0000-0003-0827-4746</orcidid><orcidid>https://orcid.org/0000-0002-0383-2342</orcidid><orcidid>https://orcid.org/0000-0003-0572-844X</orcidid><orcidid>https://orcid.org/0000-0002-3993-1561</orcidid><orcidid>https://orcid.org/0000-0002-5256-8138</orcidid><orcidid>https://orcid.org/0000-0001-9310-7840</orcidid></search><sort><creationdate>20200617</creationdate><title>The Metabolism of Epoxyeicosatrienoic Acids by Soluble Epoxide Hydrolase Is Protective against the Development of Vascular Calcification</title><author>Varennes, Olivier ; Mentaverri, Romuald ; Duflot, Thomas ; Kauffenstein, Gilles ; Objois, Thibaut ; Lenglet, Gaëlle ; Avondo, Carine ; Morisseau, Christophe ; Brazier, Michel ; Kamel, Saïd ; Six, Isabelle ; Bellien, Jeremy</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c446t-742cb9102e8cc58be2a121d7c41d7bd3a0f3e4bcdba9875d44055d6e0c4f07ed3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Alkaline phosphatase</topic><topic>Animals</topic><topic>Aorta</topic><topic>Benzoic acid</topic><topic>Bioavailability</topic><topic>Biomedical materials</topic><topic>Calcification</topic><topic>Calcification (ectopic)</topic><topic>Calcium</topic><topic>Carotid Arteries - metabolism</topic><topic>Carotid Arteries - pathology</topic><topic>Cbfa-1 protein</topic><topic>Cell Differentiation</topic><topic>Cytochrome</topic><topic>Cytochrome P450</topic><topic>Cytochromes P450</topic><topic>Disease Susceptibility</topic><topic>Endothelium</topic><topic>Endothelium - metabolism</topic><topic>Epoxide hydrolase</topic><topic>Epoxide Hydrolases - metabolism</topic><topic>Experiments</topic><topic>Fatty Acids, Monounsaturated - metabolism</topic><topic>Fluconazole</topic><topic>Gene expression</topic><topic>Humans</topic><topic>Kinases</topic><topic>Life Sciences</topic><topic>Lipid Metabolism</topic><topic>Metabolism</topic><topic>Metabolites</topic><topic>Mineralization</topic><topic>Muscles</topic><topic>Phosphatase</topic><topic>Phosphoric Monoester Hydrolases - metabolism</topic><topic>Plaques</topic><topic>Protein kinase A</topic><topic>Rats</topic><topic>RNA, Messenger - genetics</topic><topic>Smooth muscle</topic><topic>Staphylococcal enterotoxin H</topic><topic>Vascular Calcification - etiology</topic><topic>Vascular Calcification - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Varennes, Olivier</creatorcontrib><creatorcontrib>Mentaverri, Romuald</creatorcontrib><creatorcontrib>Duflot, Thomas</creatorcontrib><creatorcontrib>Kauffenstein, Gilles</creatorcontrib><creatorcontrib>Objois, Thibaut</creatorcontrib><creatorcontrib>Lenglet, Gaëlle</creatorcontrib><creatorcontrib>Avondo, Carine</creatorcontrib><creatorcontrib>Morisseau, Christophe</creatorcontrib><creatorcontrib>Brazier, Michel</creatorcontrib><creatorcontrib>Kamel, Saïd</creatorcontrib><creatorcontrib>Six, Isabelle</creatorcontrib><creatorcontrib>Bellien, Jeremy</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Research Library (Alumni Edition)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>Research Library Prep</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Research Library</collection><collection>Research Library (Corporate)</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>ProQuest Central Basic</collection><collection>MEDLINE - Academic</collection><collection>Hyper Article en Ligne (HAL)</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>International journal of molecular sciences</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Varennes, Olivier</au><au>Mentaverri, Romuald</au><au>Duflot, Thomas</au><au>Kauffenstein, Gilles</au><au>Objois, Thibaut</au><au>Lenglet, Gaëlle</au><au>Avondo, Carine</au><au>Morisseau, Christophe</au><au>Brazier, Michel</au><au>Kamel, Saïd</au><au>Six, Isabelle</au><au>Bellien, Jeremy</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The Metabolism of Epoxyeicosatrienoic Acids by Soluble Epoxide Hydrolase Is Protective against the Development of Vascular Calcification</atitle><jtitle>International journal of molecular sciences</jtitle><addtitle>Int J Mol Sci</addtitle><date>2020-06-17</date><risdate>2020</risdate><volume>21</volume><issue>12</issue><spage>4313</spage><pages>4313-</pages><issn>1422-0067</issn><issn>1661-6596</issn><eissn>1422-0067</eissn><abstract>This study addressed the hypothesis that soluble epoxide hydrolase (sEH), which metabolizes endothelium-derived epoxyeicosatrienoic acids, plays a role in vascular calcification. The sEH inhibitor
-4-(4-(3-adamantan-1-yl-ureido)-cyclohexyloxy)-benzoic acid (
-AUCB) potentiated the increase in calcium deposition of rat aortic rings cultured in high-phosphate conditions. This was associated with increased tissue-nonspecific alkaline phosphatase activity and mRNA expression level of the osteochondrogenic marker Runx2. The procalcifying effect of
-AUCB was prevented by mechanical aortic deendothelialization or inhibition of the production and action of epoxyeicosatrienoic acids using the cytochrome P450 inhibitor fluconazole and the antagonist 14,15-epoxyeicosa-5(Z)-enoic acid (14,15-EEZE), respectively. Similarly, exogenous epoxyeicosatrienoic acids potentiated the calcification of rat aortic rings through a protein kinase A (PKA)-dependent mechanism and of human aortic vascular smooth muscle cells when sEH was inhibited by
-AUCB. Finally, a global gene expression profiling analysis revealed that the mRNA expression level of sEH was decreased in human carotid calcified plaques compared to adjacent lesion-free sites and was inversely correlated with Runx2 expression. These results show that sEH hydrolase plays a protective role against vascular calcification by reducing the bioavailability of epoxyeicosatrienoic acids.</abstract><cop>Switzerland</cop><pub>MDPI AG</pub><pmid>32560362</pmid><doi>10.3390/ijms21124313</doi><orcidid>https://orcid.org/0000-0002-8730-284X</orcidid><orcidid>https://orcid.org/0000-0003-0827-4746</orcidid><orcidid>https://orcid.org/0000-0002-0383-2342</orcidid><orcidid>https://orcid.org/0000-0003-0572-844X</orcidid><orcidid>https://orcid.org/0000-0002-3993-1561</orcidid><orcidid>https://orcid.org/0000-0002-5256-8138</orcidid><orcidid>https://orcid.org/0000-0001-9310-7840</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | International journal of molecular sciences, 2020-06, Vol.21 (12), p.4313 |
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| source | MDPI - Multidisciplinary Digital Publishing Institute; MEDLINE; EZB-FREE-00999 freely available EZB journals; PubMed Central |
| subjects | Alkaline phosphatase Animals Aorta Benzoic acid Bioavailability Biomedical materials Calcification Calcification (ectopic) Calcium Carotid Arteries - metabolism Carotid Arteries - pathology Cbfa-1 protein Cell Differentiation Cytochrome Cytochrome P450 Cytochromes P450 Disease Susceptibility Endothelium Endothelium - metabolism Epoxide hydrolase Epoxide Hydrolases - metabolism Experiments Fatty Acids, Monounsaturated - metabolism Fluconazole Gene expression Humans Kinases Life Sciences Lipid Metabolism Metabolism Metabolites Mineralization Muscles Phosphatase Phosphoric Monoester Hydrolases - metabolism Plaques Protein kinase A Rats RNA, Messenger - genetics Smooth muscle Staphylococcal enterotoxin H Vascular Calcification - etiology Vascular Calcification - metabolism |
| title | The Metabolism of Epoxyeicosatrienoic Acids by Soluble Epoxide Hydrolase Is Protective against the Development of Vascular Calcification |
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