HIV antiretroviral drugs, dolutegravir, maraviroc and ritonavir-boosted atazanavir use different pathways to affect inflammation, senescence and insulin sensitivity in human coronary endothelial cells
Aging HIV-infected antiretroviral-treatment (ART)-controlled patients often present cardiovascular and metabolic comorbidities. Thus, it is mandatory that life-long used ART has no cardiometabolic toxicity. Protease inhibitors have been associated with cardiometabolic risk, integrase-strand-transfer...
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| description | Aging HIV-infected antiretroviral-treatment (ART)-controlled patients often present cardiovascular and metabolic comorbidities. Thus, it is mandatory that life-long used ART has no cardiometabolic toxicity. Protease inhibitors have been associated with cardiometabolic risk, integrase-strand-transfer-inhibitors (INSTI) with weight gain and the CCR5 inhibitor maraviroc with improved vascular function. We have previously reported that the INSTI dolutegravir and maraviroc improved, and ritonavir-boosted atazanavir(atazanavir/r) worsened, inflammation and senescence in human coronary artery endothelial cells (HCAEC)s from adult controls. Here, we analyzed the pathways involved in the drugs' effects on inflammation, senescence and also insulin resistance.
We analyzed the involvement of the anti-inflammatory SIRT-1 pathway in HCAECs. Then, we performed a transcriptomic analysis of the effect of dolutegravir, maraviroc and atazanavir/r and used siRNA-silencing to address ubiquitin-specific-peptidase-18 (USP18) involvement into ART effects.
Dolutegravir reduced inflammation by decreasing NFκB activation and IL-6/IL-8/sICAM-1/sVCAM-1 secretion, as did maraviroc with a milder effect. However, when SIRT-1 was inhibited by splitomicin, the drugs anti-inflammatory effects were maintained, indicating that they were SIRT-1-independant. From the transcriptomic analysis we selected USP18, previously shown to decrease inflammation and insulin-resistance. USP18-silencing enhanced basal inflammation and senescence. Maraviroc still inhibited NFκB activation, cytokine/adhesion molecules secretion and senescence but the effects of dolutegravir and atazanavir/r were lost, suggesting that they involved USP18. Otherwise, in HCAECs, dolutegravir improved and atazanavir/r worsened insulin resistance while maraviroc had no effect. In USP18-silenced cells, basal insulin resistance was increased, but dolutegravir and atazanavir/r kept their effect on insulin sensitivity, indicating that USP18 was dispensable.
USP18 reduced basal inflammation, senescence and insulin resistance in coronary endothelial cells. Dolutegravir and atazanavir/r, but not maraviroc, exerted opposite effects on inflammation and senescence that involved USP18. Otherwise, dolutegravir improved and atazanavir/r worsened insulin resistance independently of USP18. Thus, in endothelial cells, dolutegravir and atazanavir/r oppositely affected pathways leading to inflammation, senescence and insulin resistance. |
| doi_str_mv | 10.1371/journal.pone.0226924 |
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We analyzed the involvement of the anti-inflammatory SIRT-1 pathway in HCAECs. Then, we performed a transcriptomic analysis of the effect of dolutegravir, maraviroc and atazanavir/r and used siRNA-silencing to address ubiquitin-specific-peptidase-18 (USP18) involvement into ART effects.
Dolutegravir reduced inflammation by decreasing NFκB activation and IL-6/IL-8/sICAM-1/sVCAM-1 secretion, as did maraviroc with a milder effect. However, when SIRT-1 was inhibited by splitomicin, the drugs anti-inflammatory effects were maintained, indicating that they were SIRT-1-independant. From the transcriptomic analysis we selected USP18, previously shown to decrease inflammation and insulin-resistance. USP18-silencing enhanced basal inflammation and senescence. Maraviroc still inhibited NFκB activation, cytokine/adhesion molecules secretion and senescence but the effects of dolutegravir and atazanavir/r were lost, suggesting that they involved USP18. Otherwise, in HCAECs, dolutegravir improved and atazanavir/r worsened insulin resistance while maraviroc had no effect. In USP18-silenced cells, basal insulin resistance was increased, but dolutegravir and atazanavir/r kept their effect on insulin sensitivity, indicating that USP18 was dispensable.
USP18 reduced basal inflammation, senescence and insulin resistance in coronary endothelial cells. Dolutegravir and atazanavir/r, but not maraviroc, exerted opposite effects on inflammation and senescence that involved USP18. Otherwise, dolutegravir improved and atazanavir/r worsened insulin resistance independently of USP18. Thus, in endothelial cells, dolutegravir and atazanavir/r oppositely affected pathways leading to inflammation, senescence and insulin resistance.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0226924</identifier><identifier>PMID: 31971958</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Activation ; Aging ; Analysis ; Anti-HIV agents ; Anti-HIV Agents - adverse effects ; Anti-HIV Agents - therapeutic use ; Anti-inflammatory agents ; Antiretroviral agents ; Antiretroviral drugs ; Antiretroviral therapy ; Antiviral drugs ; Atazanavir ; Atazanavir Sulfate - adverse effects ; Atazanavir Sulfate - therapeutic use ; Biology and Life Sciences ; Cardiac patients ; CCR5 protein ; Cells, Cultured ; Comorbidity ; Coronary artery ; Coronary vessels ; Coronary Vessels - cytology ; Coronary Vessels - drug effects ; Coronary Vessels - metabolism ; Cytokines ; Darunavir ; Diabetes therapy ; Dolutegravir ; Drug therapy ; Drugs ; Endothelial cells ; Endothelial Cells - cytology ; Endothelial Cells - drug effects ; Endothelial Cells - metabolism ; Endothelium ; Evaluation ; Female ; Health risks ; Heterocyclic Compounds, 3-Ring - adverse effects ; Heterocyclic Compounds, 3-Ring - therapeutic use ; Highly active antiretroviral therapy ; HIV ; HIV Infections - drug therapy ; Human health and pathology ; Human immunodeficiency virus ; Humans ; Infectious diseases ; Inflammation ; Insulin ; Insulin Resistance ; Integrase ; Interleukin 6 ; Interleukin 8 ; Life Sciences ; Lopinavir ; Male ; Maraviroc ; Maraviroc - adverse effects ; Maraviroc - therapeutic use ; Medicine and Health Sciences ; Metabolism ; NF-kappa B - metabolism ; NF-κB protein ; Nutrition ; Peptidase ; Pharmaceutical sciences ; Pharmacology ; Protease inhibitors ; Proteases ; Proteinase inhibitors ; Raltegravir ; Ritonavir ; Ritonavir - adverse effects ; Ritonavir - therapeutic use ; Senescence ; Sensitivity ; Signal Transduction ; siRNA ; Sirtuin 1 - metabolism ; Toxicity ; Ubiquitin ; Ubiquitin Thiolesterase - genetics ; Ubiquitin Thiolesterase - metabolism ; USP18 protein ; Veins & arteries</subject><ispartof>PloS one, 2020-01, Vol.15 (1), p.e0226924</ispartof><rights>COPYRIGHT 2020 Public Library of Science</rights><rights>2020 Auclair et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 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 Auclair et al 2020 Auclair et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c729t-67a319893f87f9628d60cb3161b6e7d6e8c7a893fa82358143b302a90efa6c0c3</citedby><cites>FETCH-LOGICAL-c729t-67a319893f87f9628d60cb3161b6e7d6e8c7a893fa82358143b302a90efa6c0c3</cites><orcidid>0000-0002-1710-4186 ; 0000-0003-0086-4821</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/PMC6977740/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6977740/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79343,79344</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31971958$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://inserm.hal.science/inserm-02474042$$DView record in HAL$$Hfree_for_read</backlink></links><search><creatorcontrib>Auclair, Martine</creatorcontrib><creatorcontrib>Guénantin, Anne-Claire</creatorcontrib><creatorcontrib>Fellahi, Soraya</creatorcontrib><creatorcontrib>Garcia, Marie</creatorcontrib><creatorcontrib>Capeau, Jacqueline</creatorcontrib><title>HIV antiretroviral drugs, dolutegravir, maraviroc and ritonavir-boosted atazanavir use different pathways to affect inflammation, senescence and insulin sensitivity in human coronary endothelial cells</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Aging HIV-infected antiretroviral-treatment (ART)-controlled patients often present cardiovascular and metabolic comorbidities. Thus, it is mandatory that life-long used ART has no cardiometabolic toxicity. Protease inhibitors have been associated with cardiometabolic risk, integrase-strand-transfer-inhibitors (INSTI) with weight gain and the CCR5 inhibitor maraviroc with improved vascular function. We have previously reported that the INSTI dolutegravir and maraviroc improved, and ritonavir-boosted atazanavir(atazanavir/r) worsened, inflammation and senescence in human coronary artery endothelial cells (HCAEC)s from adult controls. Here, we analyzed the pathways involved in the drugs' effects on inflammation, senescence and also insulin resistance.
We analyzed the involvement of the anti-inflammatory SIRT-1 pathway in HCAECs. Then, we performed a transcriptomic analysis of the effect of dolutegravir, maraviroc and atazanavir/r and used siRNA-silencing to address ubiquitin-specific-peptidase-18 (USP18) involvement into ART effects.
Dolutegravir reduced inflammation by decreasing NFκB activation and IL-6/IL-8/sICAM-1/sVCAM-1 secretion, as did maraviroc with a milder effect. However, when SIRT-1 was inhibited by splitomicin, the drugs anti-inflammatory effects were maintained, indicating that they were SIRT-1-independant. From the transcriptomic analysis we selected USP18, previously shown to decrease inflammation and insulin-resistance. USP18-silencing enhanced basal inflammation and senescence. Maraviroc still inhibited NFκB activation, cytokine/adhesion molecules secretion and senescence but the effects of dolutegravir and atazanavir/r were lost, suggesting that they involved USP18. Otherwise, in HCAECs, dolutegravir improved and atazanavir/r worsened insulin resistance while maraviroc had no effect. In USP18-silenced cells, basal insulin resistance was increased, but dolutegravir and atazanavir/r kept their effect on insulin sensitivity, indicating that USP18 was dispensable.
USP18 reduced basal inflammation, senescence and insulin resistance in coronary endothelial cells. Dolutegravir and atazanavir/r, but not maraviroc, exerted opposite effects on inflammation and senescence that involved USP18. Otherwise, dolutegravir improved and atazanavir/r worsened insulin resistance independently of USP18. Thus, in endothelial cells, dolutegravir and atazanavir/r oppositely affected pathways leading to inflammation, senescence and insulin resistance.</description><subject>Activation</subject><subject>Aging</subject><subject>Analysis</subject><subject>Anti-HIV agents</subject><subject>Anti-HIV Agents - adverse effects</subject><subject>Anti-HIV Agents - therapeutic use</subject><subject>Anti-inflammatory agents</subject><subject>Antiretroviral agents</subject><subject>Antiretroviral drugs</subject><subject>Antiretroviral therapy</subject><subject>Antiviral drugs</subject><subject>Atazanavir</subject><subject>Atazanavir Sulfate - adverse effects</subject><subject>Atazanavir Sulfate - therapeutic use</subject><subject>Biology and Life Sciences</subject><subject>Cardiac patients</subject><subject>CCR5 protein</subject><subject>Cells, Cultured</subject><subject>Comorbidity</subject><subject>Coronary artery</subject><subject>Coronary vessels</subject><subject>Coronary Vessels - cytology</subject><subject>Coronary Vessels - drug effects</subject><subject>Coronary Vessels - metabolism</subject><subject>Cytokines</subject><subject>Darunavir</subject><subject>Diabetes therapy</subject><subject>Dolutegravir</subject><subject>Drug therapy</subject><subject>Drugs</subject><subject>Endothelial cells</subject><subject>Endothelial Cells - cytology</subject><subject>Endothelial Cells - drug effects</subject><subject>Endothelial Cells - metabolism</subject><subject>Endothelium</subject><subject>Evaluation</subject><subject>Female</subject><subject>Health risks</subject><subject>Heterocyclic Compounds, 3-Ring - adverse effects</subject><subject>Heterocyclic Compounds, 3-Ring - therapeutic use</subject><subject>Highly active antiretroviral therapy</subject><subject>HIV</subject><subject>HIV Infections - drug therapy</subject><subject>Human health and pathology</subject><subject>Human immunodeficiency virus</subject><subject>Humans</subject><subject>Infectious diseases</subject><subject>Inflammation</subject><subject>Insulin</subject><subject>Insulin Resistance</subject><subject>Integrase</subject><subject>Interleukin 6</subject><subject>Interleukin 8</subject><subject>Life Sciences</subject><subject>Lopinavir</subject><subject>Male</subject><subject>Maraviroc</subject><subject>Maraviroc - adverse effects</subject><subject>Maraviroc - therapeutic use</subject><subject>Medicine and Health Sciences</subject><subject>Metabolism</subject><subject>NF-kappa B - metabolism</subject><subject>NF-κB protein</subject><subject>Nutrition</subject><subject>Peptidase</subject><subject>Pharmaceutical sciences</subject><subject>Pharmacology</subject><subject>Protease inhibitors</subject><subject>Proteases</subject><subject>Proteinase inhibitors</subject><subject>Raltegravir</subject><subject>Ritonavir</subject><subject>Ritonavir - adverse effects</subject><subject>Ritonavir - therapeutic use</subject><subject>Senescence</subject><subject>Sensitivity</subject><subject>Signal Transduction</subject><subject>siRNA</subject><subject>Sirtuin 1 - metabolism</subject><subject>Toxicity</subject><subject>Ubiquitin</subject><subject>Ubiquitin Thiolesterase - genetics</subject><subject>Ubiquitin Thiolesterase - metabolism</subject><subject>USP18 protein</subject><subject>Veins & arteries</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNqNk1uL1DAUx4so7rr6DUQDgiDMjLl0kvZFGBZ1BxYWvOxryCSn0yxtMibp6PgJ_VhmLrvsiIL0oek_v3NOz60onhM8IUyQtzd-CE51k5V3MMGU8pqWD4pTUjM65hSzh_fOJ8WTGG8wnrKK88fFCSO1IPW0Oi1-XcyvkXLJBkjBr21QHTJhWMYRMr4bEiyDyuoI9Wp38DrTBgWbvNt-jxfexwQGqaR-qp2EhgjI2KaBAC6hlUrtd7WJKHmksqgTsq7pVN-rZL0boQgOoganYefaujh01m3laJNd27TJGmqHXjmkfchxwwaBMz610Nn8vxq6Lj4tHjWqi_Ds8D4rvn54_-X8Ynx59XF-Prsca0HrNOZC5eSrmjWVaGpOK8OxXjDCyYKDMBwqLdT2WlWUTStSsgXDVNUYGsU11uyseLn3u-p8lIcmRElZWVI8JVORifmeMF7dyFWwuXQb6ZWVO8GHpVQhWd2BFHU9VYSUvKmmZQlMCWYMXUApypIZgOzr3SHasOjB5Cql3KEjp8c3zrZy6deS10KIEmcHo72D9g-zi9mlzKWG0EtMczxc0jXJ-KtDvOC_DRDTPzI8UEuVk8jd9Dm27m3UcsYJxVVViTpTk79Q-THQW52ntrFZPzJ4c2SQmQQ_0lINMcr550__z15dH7Ov77EtqC61cTvcefziMVjuQR18jAGau4oRLLdLd1sNuV06eVi6bPbifpPujG63jP0GdS4snQ</recordid><startdate>20200123</startdate><enddate>20200123</enddate><creator>Auclair, Martine</creator><creator>Guénantin, Anne-Claire</creator><creator>Fellahi, Soraya</creator><creator>Garcia, Marie</creator><creator>Capeau, Jacqueline</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</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>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>1XC</scope><scope>VOOES</scope><scope>5PM</scope><scope>DOA</scope><orcidid>https://orcid.org/0000-0002-1710-4186</orcidid><orcidid>https://orcid.org/0000-0003-0086-4821</orcidid></search><sort><creationdate>20200123</creationdate><title>HIV antiretroviral drugs, dolutegravir, maraviroc and ritonavir-boosted atazanavir use different pathways to affect inflammation, senescence and insulin sensitivity in human coronary endothelial cells</title><author>Auclair, Martine ; Guénantin, Anne-Claire ; Fellahi, Soraya ; Garcia, Marie ; Capeau, Jacqueline</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c729t-67a319893f87f9628d60cb3161b6e7d6e8c7a893fa82358143b302a90efa6c0c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Activation</topic><topic>Aging</topic><topic>Analysis</topic><topic>Anti-HIV agents</topic><topic>Anti-HIV Agents - adverse effects</topic><topic>Anti-HIV Agents - therapeutic use</topic><topic>Anti-inflammatory agents</topic><topic>Antiretroviral agents</topic><topic>Antiretroviral drugs</topic><topic>Antiretroviral therapy</topic><topic>Antiviral drugs</topic><topic>Atazanavir</topic><topic>Atazanavir Sulfate - adverse effects</topic><topic>Atazanavir Sulfate - therapeutic use</topic><topic>Biology and Life Sciences</topic><topic>Cardiac patients</topic><topic>CCR5 protein</topic><topic>Cells, Cultured</topic><topic>Comorbidity</topic><topic>Coronary artery</topic><topic>Coronary vessels</topic><topic>Coronary Vessels - cytology</topic><topic>Coronary Vessels - drug effects</topic><topic>Coronary Vessels - metabolism</topic><topic>Cytokines</topic><topic>Darunavir</topic><topic>Diabetes therapy</topic><topic>Dolutegravir</topic><topic>Drug therapy</topic><topic>Drugs</topic><topic>Endothelial cells</topic><topic>Endothelial Cells - cytology</topic><topic>Endothelial Cells - drug effects</topic><topic>Endothelial Cells - metabolism</topic><topic>Endothelium</topic><topic>Evaluation</topic><topic>Female</topic><topic>Health risks</topic><topic>Heterocyclic Compounds, 3-Ring - adverse effects</topic><topic>Heterocyclic Compounds, 3-Ring - therapeutic use</topic><topic>Highly active antiretroviral therapy</topic><topic>HIV</topic><topic>HIV Infections - drug therapy</topic><topic>Human health and pathology</topic><topic>Human immunodeficiency virus</topic><topic>Humans</topic><topic>Infectious diseases</topic><topic>Inflammation</topic><topic>Insulin</topic><topic>Insulin Resistance</topic><topic>Integrase</topic><topic>Interleukin 6</topic><topic>Interleukin 8</topic><topic>Life Sciences</topic><topic>Lopinavir</topic><topic>Male</topic><topic>Maraviroc</topic><topic>Maraviroc - adverse effects</topic><topic>Maraviroc - therapeutic use</topic><topic>Medicine and Health Sciences</topic><topic>Metabolism</topic><topic>NF-kappa B - metabolism</topic><topic>NF-κB protein</topic><topic>Nutrition</topic><topic>Peptidase</topic><topic>Pharmaceutical sciences</topic><topic>Pharmacology</topic><topic>Protease inhibitors</topic><topic>Proteases</topic><topic>Proteinase inhibitors</topic><topic>Raltegravir</topic><topic>Ritonavir</topic><topic>Ritonavir - adverse effects</topic><topic>Ritonavir - therapeutic use</topic><topic>Senescence</topic><topic>Sensitivity</topic><topic>Signal Transduction</topic><topic>siRNA</topic><topic>Sirtuin 1 - metabolism</topic><topic>Toxicity</topic><topic>Ubiquitin</topic><topic>Ubiquitin Thiolesterase - genetics</topic><topic>Ubiquitin Thiolesterase - metabolism</topic><topic>USP18 protein</topic><topic>Veins & arteries</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Auclair, Martine</creatorcontrib><creatorcontrib>Guénantin, Anne-Claire</creatorcontrib><creatorcontrib>Fellahi, Soraya</creatorcontrib><creatorcontrib>Garcia, Marie</creatorcontrib><creatorcontrib>Capeau, Jacqueline</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Opposing Viewpoints in Context (Gale)</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Proquest Nursing & Allied Health Source</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Meteorological & Geoastrophysical Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Agricultural Science Collection</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Materials Science & Engineering Collection</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest One Sustainability</collection><collection>ProQuest Central UK/Ireland</collection><collection>Advanced Technologies & Aerospace Collection</collection><collection>Agricultural & Environmental Science Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Technology Collection</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Materials Science Collection</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Materials Science Database</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Meteorological & Geoastrophysical Abstracts - Academic</collection><collection>ProQuest Engineering Collection</collection><collection>ProQuest Biological Science Collection</collection><collection>Agricultural Science Database</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Engineering Database</collection><collection>Nursing & Allied Health Premium</collection><collection>Advanced Technologies & Aerospace Database</collection><collection>ProQuest Advanced Technologies & Aerospace Collection</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Environmental Science Database</collection><collection>Materials Science Collection</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>Engineering Collection</collection><collection>Environmental Science Collection</collection><collection>Genetics Abstracts</collection><collection>Hyper Article en Ligne (HAL)</collection><collection>Hyper Article en Ligne (HAL) (Open Access)</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Auclair, Martine</au><au>Guénantin, Anne-Claire</au><au>Fellahi, Soraya</au><au>Garcia, Marie</au><au>Capeau, Jacqueline</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>HIV antiretroviral drugs, dolutegravir, maraviroc and ritonavir-boosted atazanavir use different pathways to affect inflammation, senescence and insulin sensitivity in human coronary endothelial cells</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2020-01-23</date><risdate>2020</risdate><volume>15</volume><issue>1</issue><spage>e0226924</spage><pages>e0226924-</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Aging HIV-infected antiretroviral-treatment (ART)-controlled patients often present cardiovascular and metabolic comorbidities. Thus, it is mandatory that life-long used ART has no cardiometabolic toxicity. Protease inhibitors have been associated with cardiometabolic risk, integrase-strand-transfer-inhibitors (INSTI) with weight gain and the CCR5 inhibitor maraviroc with improved vascular function. We have previously reported that the INSTI dolutegravir and maraviroc improved, and ritonavir-boosted atazanavir(atazanavir/r) worsened, inflammation and senescence in human coronary artery endothelial cells (HCAEC)s from adult controls. Here, we analyzed the pathways involved in the drugs' effects on inflammation, senescence and also insulin resistance.
We analyzed the involvement of the anti-inflammatory SIRT-1 pathway in HCAECs. Then, we performed a transcriptomic analysis of the effect of dolutegravir, maraviroc and atazanavir/r and used siRNA-silencing to address ubiquitin-specific-peptidase-18 (USP18) involvement into ART effects.
Dolutegravir reduced inflammation by decreasing NFκB activation and IL-6/IL-8/sICAM-1/sVCAM-1 secretion, as did maraviroc with a milder effect. However, when SIRT-1 was inhibited by splitomicin, the drugs anti-inflammatory effects were maintained, indicating that they were SIRT-1-independant. From the transcriptomic analysis we selected USP18, previously shown to decrease inflammation and insulin-resistance. USP18-silencing enhanced basal inflammation and senescence. Maraviroc still inhibited NFκB activation, cytokine/adhesion molecules secretion and senescence but the effects of dolutegravir and atazanavir/r were lost, suggesting that they involved USP18. Otherwise, in HCAECs, dolutegravir improved and atazanavir/r worsened insulin resistance while maraviroc had no effect. In USP18-silenced cells, basal insulin resistance was increased, but dolutegravir and atazanavir/r kept their effect on insulin sensitivity, indicating that USP18 was dispensable.
USP18 reduced basal inflammation, senescence and insulin resistance in coronary endothelial cells. Dolutegravir and atazanavir/r, but not maraviroc, exerted opposite effects on inflammation and senescence that involved USP18. Otherwise, dolutegravir improved and atazanavir/r worsened insulin resistance independently of USP18. Thus, in endothelial cells, dolutegravir and atazanavir/r oppositely affected pathways leading to inflammation, senescence and insulin resistance.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>31971958</pmid><doi>10.1371/journal.pone.0226924</doi><tpages>e0226924</tpages><orcidid>https://orcid.org/0000-0002-1710-4186</orcidid><orcidid>https://orcid.org/0000-0003-0086-4821</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2020-01, Vol.15 (1), p.e0226924 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_2344205157 |
| source | Public Library of Science (PLoS) Journals Open Access; MEDLINE; DOAJ Directory of Open Access Journals; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Activation Aging Analysis Anti-HIV agents Anti-HIV Agents - adverse effects Anti-HIV Agents - therapeutic use Anti-inflammatory agents Antiretroviral agents Antiretroviral drugs Antiretroviral therapy Antiviral drugs Atazanavir Atazanavir Sulfate - adverse effects Atazanavir Sulfate - therapeutic use Biology and Life Sciences Cardiac patients CCR5 protein Cells, Cultured Comorbidity Coronary artery Coronary vessels Coronary Vessels - cytology Coronary Vessels - drug effects Coronary Vessels - metabolism Cytokines Darunavir Diabetes therapy Dolutegravir Drug therapy Drugs Endothelial cells Endothelial Cells - cytology Endothelial Cells - drug effects Endothelial Cells - metabolism Endothelium Evaluation Female Health risks Heterocyclic Compounds, 3-Ring - adverse effects Heterocyclic Compounds, 3-Ring - therapeutic use Highly active antiretroviral therapy HIV HIV Infections - drug therapy Human health and pathology Human immunodeficiency virus Humans Infectious diseases Inflammation Insulin Insulin Resistance Integrase Interleukin 6 Interleukin 8 Life Sciences Lopinavir Male Maraviroc Maraviroc - adverse effects Maraviroc - therapeutic use Medicine and Health Sciences Metabolism NF-kappa B - metabolism NF-κB protein Nutrition Peptidase Pharmaceutical sciences Pharmacology Protease inhibitors Proteases Proteinase inhibitors Raltegravir Ritonavir Ritonavir - adverse effects Ritonavir - therapeutic use Senescence Sensitivity Signal Transduction siRNA Sirtuin 1 - metabolism Toxicity Ubiquitin Ubiquitin Thiolesterase - genetics Ubiquitin Thiolesterase - metabolism USP18 protein Veins & arteries |
| title | HIV antiretroviral drugs, dolutegravir, maraviroc and ritonavir-boosted atazanavir use different pathways to affect inflammation, senescence and insulin sensitivity in human coronary endothelial cells |
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