Canagliflozin inhibits interleukin-1β-stimulated cytokine and chemokine secretion in vascular endothelial cells by AMP-activated protein kinase-dependent and -independent mechanisms
Recent clinical trials of the hypoglycaemic sodium-glucose co-transporter-2 (SGLT2) inhibitors, which inhibit renal glucose reabsorption, have reported beneficial cardiovascular outcomes. Whether SGLT2 inhibitors directly affect cardiovascular tissues, however, remains unclear. We have previously re...
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description | Recent clinical trials of the hypoglycaemic sodium-glucose co-transporter-2 (SGLT2) inhibitors, which inhibit renal glucose reabsorption, have reported beneficial cardiovascular outcomes. Whether SGLT2 inhibitors directly affect cardiovascular tissues, however, remains unclear. We have previously reported that the SGLT2 inhibitor canagliflozin activates AMP-activated protein kinase (AMPK) in immortalised cell lines and murine hepatocytes. As AMPK has anti-inflammatory actions in vascular cells, we examined whether SGLT2 inhibitors attenuated inflammatory signalling in cultured human endothelial cells. Incubation with clinically-relevant concentrations of canagliflozin, but not empagliflozin or dapagliflozin activated AMPK and inhibited IL-1β-stimulated adhesion of pro-monocytic U937 cells and secretion of IL-6 and monocyte chemoattractant protein-1 (MCP-1). Inhibition of MCP-1 secretion was attenuated by expression of dominant-negative AMPK and was mimicked by the direct AMPK activator, A769662. Stimulation of cells with either canagliflozin or A769662 had no effect on IL-1β-stimulated cell surface levels of adhesion molecules or nuclear factor-κB signalling. Despite these identical effects of canagliflozin and A769662, IL-1β-stimulated IL-6/MCP-1 mRNA was inhibited by canagliflozin, but not A769662, whereas IL-1β-stimulated c-jun N-terminal kinase phosphorylation was inhibited by A769662, but not canagliflozin. These data indicate that clinically-relevant canagliflozin concentrations directly inhibit endothelial pro-inflammatory chemokine/cytokine secretion by AMPK-dependent and -independent mechanisms without affecting early IL-1β signalling. |
doi_str_mv | 10.1038/s41598-018-23420-4 |
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Whether SGLT2 inhibitors directly affect cardiovascular tissues, however, remains unclear. We have previously reported that the SGLT2 inhibitor canagliflozin activates AMP-activated protein kinase (AMPK) in immortalised cell lines and murine hepatocytes. As AMPK has anti-inflammatory actions in vascular cells, we examined whether SGLT2 inhibitors attenuated inflammatory signalling in cultured human endothelial cells. Incubation with clinically-relevant concentrations of canagliflozin, but not empagliflozin or dapagliflozin activated AMPK and inhibited IL-1β-stimulated adhesion of pro-monocytic U937 cells and secretion of IL-6 and monocyte chemoattractant protein-1 (MCP-1). Inhibition of MCP-1 secretion was attenuated by expression of dominant-negative AMPK and was mimicked by the direct AMPK activator, A769662. Stimulation of cells with either canagliflozin or A769662 had no effect on IL-1β-stimulated cell surface levels of adhesion molecules or nuclear factor-κB signalling. Despite these identical effects of canagliflozin and A769662, IL-1β-stimulated IL-6/MCP-1 mRNA was inhibited by canagliflozin, but not A769662, whereas IL-1β-stimulated c-jun N-terminal kinase phosphorylation was inhibited by A769662, but not canagliflozin. These data indicate that clinically-relevant canagliflozin concentrations directly inhibit endothelial pro-inflammatory chemokine/cytokine secretion by AMPK-dependent and -independent mechanisms without affecting early IL-1β signalling.</description><identifier>ISSN: 2045-2322</identifier><identifier>EISSN: 2045-2322</identifier><identifier>DOI: 10.1038/s41598-018-23420-4</identifier><identifier>PMID: 29588466</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13/1 ; 13/106 ; 13/31 ; 13/95 ; 14 ; 631/45 ; 631/80/86 ; 96 ; Adhesion ; AMP ; AMP-activated protein kinase ; AMP-Activated Protein Kinases - immunology ; Animals ; Anti-Inflammatory Agents - pharmacology ; c-Jun protein ; Canagliflozin - pharmacology ; Cell adhesion molecules ; Cell lines ; Cell surface ; Cells, Cultured ; Chemokines ; Chemokines - immunology ; Clinical trials ; Cytokines ; Cytokines - immunology ; Endothelial cells ; Endothelial Cells - drug effects ; Endothelial Cells - immunology ; Glucose transporter ; Hepatocytes ; Human Umbilical Vein Endothelial Cells ; Humanities and Social Sciences ; Humans ; Inflammation ; Inhibitors ; Interleukin 6 ; Interleukin-1beta - antagonists & inhibitors ; Interleukin-1beta - immunology ; JNK protein ; Kinases ; Mice ; Monocyte chemoattractant protein ; Monocyte chemoattractant protein 1 ; Monocytes ; mRNA ; multidisciplinary ; Phosphorylation ; Proteins ; Reabsorption ; Science ; Science (multidisciplinary) ; Sodium ; Sodium-Glucose Transporter 2 Inhibitors - pharmacology ; Transcription factors</subject><ispartof>Scientific reports, 2018-03, Vol.8 (1), p.5276-14, Article 5276</ispartof><rights>The Author(s) 2018</rights><rights>2018. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c474t-e03c14043d9379c2ff6090edcd7cc371f628998f594c1ebd854bd7bf267857ca3</citedby><cites>FETCH-LOGICAL-c474t-e03c14043d9379c2ff6090edcd7cc371f628998f594c1ebd854bd7bf267857ca3</cites><orcidid>0000-0003-0887-5840 ; 0000-0003-0055-3724</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/PMC5869674/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5869674/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,27924,27925,41120,42189,51576,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29588466$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Mancini, Sarah J.</creatorcontrib><creatorcontrib>Boyd, Daria</creatorcontrib><creatorcontrib>Katwan, Omar J.</creatorcontrib><creatorcontrib>Strembitska, Anastasiya</creatorcontrib><creatorcontrib>Almabrouk, Tarek A.</creatorcontrib><creatorcontrib>Kennedy, Simon</creatorcontrib><creatorcontrib>Palmer, Timothy M.</creatorcontrib><creatorcontrib>Salt, Ian P.</creatorcontrib><title>Canagliflozin inhibits interleukin-1β-stimulated cytokine and chemokine secretion in vascular endothelial cells by AMP-activated protein kinase-dependent and -independent mechanisms</title><title>Scientific reports</title><addtitle>Sci Rep</addtitle><addtitle>Sci Rep</addtitle><description>Recent clinical trials of the hypoglycaemic sodium-glucose co-transporter-2 (SGLT2) inhibitors, which inhibit renal glucose reabsorption, have reported beneficial cardiovascular outcomes. Whether SGLT2 inhibitors directly affect cardiovascular tissues, however, remains unclear. We have previously reported that the SGLT2 inhibitor canagliflozin activates AMP-activated protein kinase (AMPK) in immortalised cell lines and murine hepatocytes. As AMPK has anti-inflammatory actions in vascular cells, we examined whether SGLT2 inhibitors attenuated inflammatory signalling in cultured human endothelial cells. Incubation with clinically-relevant concentrations of canagliflozin, but not empagliflozin or dapagliflozin activated AMPK and inhibited IL-1β-stimulated adhesion of pro-monocytic U937 cells and secretion of IL-6 and monocyte chemoattractant protein-1 (MCP-1). Inhibition of MCP-1 secretion was attenuated by expression of dominant-negative AMPK and was mimicked by the direct AMPK activator, A769662. Stimulation of cells with either canagliflozin or A769662 had no effect on IL-1β-stimulated cell surface levels of adhesion molecules or nuclear factor-κB signalling. Despite these identical effects of canagliflozin and A769662, IL-1β-stimulated IL-6/MCP-1 mRNA was inhibited by canagliflozin, but not A769662, whereas IL-1β-stimulated c-jun N-terminal kinase phosphorylation was inhibited by A769662, but not canagliflozin. These data indicate that clinically-relevant canagliflozin concentrations directly inhibit endothelial pro-inflammatory chemokine/cytokine secretion by AMPK-dependent and -independent mechanisms without affecting early IL-1β signalling.</description><subject>13/1</subject><subject>13/106</subject><subject>13/31</subject><subject>13/95</subject><subject>14</subject><subject>631/45</subject><subject>631/80/86</subject><subject>96</subject><subject>Adhesion</subject><subject>AMP</subject><subject>AMP-activated protein kinase</subject><subject>AMP-Activated Protein Kinases - immunology</subject><subject>Animals</subject><subject>Anti-Inflammatory Agents - pharmacology</subject><subject>c-Jun protein</subject><subject>Canagliflozin - pharmacology</subject><subject>Cell adhesion molecules</subject><subject>Cell lines</subject><subject>Cell surface</subject><subject>Cells, Cultured</subject><subject>Chemokines</subject><subject>Chemokines - immunology</subject><subject>Clinical trials</subject><subject>Cytokines</subject><subject>Cytokines - 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pharmacology</topic><topic>Transcription factors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Mancini, Sarah J.</creatorcontrib><creatorcontrib>Boyd, Daria</creatorcontrib><creatorcontrib>Katwan, Omar J.</creatorcontrib><creatorcontrib>Strembitska, Anastasiya</creatorcontrib><creatorcontrib>Almabrouk, Tarek A.</creatorcontrib><creatorcontrib>Kennedy, Simon</creatorcontrib><creatorcontrib>Palmer, Timothy M.</creatorcontrib><creatorcontrib>Salt, Ian P.</creatorcontrib><collection>Springer Nature OA Free Journals</collection><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>Biology Database (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Science Database (Alumni Edition)</collection><collection>ProQuest SciTech 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>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</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>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Science Database</collection><collection>Biological Science Database</collection><collection>Access via ProQuest (Open Access)</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 Basic</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Scientific reports</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Mancini, Sarah J.</au><au>Boyd, Daria</au><au>Katwan, Omar J.</au><au>Strembitska, Anastasiya</au><au>Almabrouk, Tarek A.</au><au>Kennedy, Simon</au><au>Palmer, Timothy M.</au><au>Salt, Ian P.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Canagliflozin inhibits interleukin-1β-stimulated cytokine and chemokine secretion in vascular endothelial cells by AMP-activated protein kinase-dependent and -independent mechanisms</atitle><jtitle>Scientific reports</jtitle><stitle>Sci Rep</stitle><addtitle>Sci Rep</addtitle><date>2018-03-27</date><risdate>2018</risdate><volume>8</volume><issue>1</issue><spage>5276</spage><epage>14</epage><pages>5276-14</pages><artnum>5276</artnum><issn>2045-2322</issn><eissn>2045-2322</eissn><abstract>Recent clinical trials of the hypoglycaemic sodium-glucose co-transporter-2 (SGLT2) inhibitors, which inhibit renal glucose reabsorption, have reported beneficial cardiovascular outcomes. Whether SGLT2 inhibitors directly affect cardiovascular tissues, however, remains unclear. We have previously reported that the SGLT2 inhibitor canagliflozin activates AMP-activated protein kinase (AMPK) in immortalised cell lines and murine hepatocytes. As AMPK has anti-inflammatory actions in vascular cells, we examined whether SGLT2 inhibitors attenuated inflammatory signalling in cultured human endothelial cells. Incubation with clinically-relevant concentrations of canagliflozin, but not empagliflozin or dapagliflozin activated AMPK and inhibited IL-1β-stimulated adhesion of pro-monocytic U937 cells and secretion of IL-6 and monocyte chemoattractant protein-1 (MCP-1). Inhibition of MCP-1 secretion was attenuated by expression of dominant-negative AMPK and was mimicked by the direct AMPK activator, A769662. Stimulation of cells with either canagliflozin or A769662 had no effect on IL-1β-stimulated cell surface levels of adhesion molecules or nuclear factor-κB signalling. Despite these identical effects of canagliflozin and A769662, IL-1β-stimulated IL-6/MCP-1 mRNA was inhibited by canagliflozin, but not A769662, whereas IL-1β-stimulated c-jun N-terminal kinase phosphorylation was inhibited by A769662, but not canagliflozin. These data indicate that clinically-relevant canagliflozin concentrations directly inhibit endothelial pro-inflammatory chemokine/cytokine secretion by AMPK-dependent and -independent mechanisms without affecting early IL-1β signalling.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>29588466</pmid><doi>10.1038/s41598-018-23420-4</doi><tpages>14</tpages><orcidid>https://orcid.org/0000-0003-0887-5840</orcidid><orcidid>https://orcid.org/0000-0003-0055-3724</orcidid><oa>free_for_read</oa></addata></record> |
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subjects | 13/1 13/106 13/31 13/95 14 631/45 631/80/86 96 Adhesion AMP AMP-activated protein kinase AMP-Activated Protein Kinases - immunology Animals Anti-Inflammatory Agents - pharmacology c-Jun protein Canagliflozin - pharmacology Cell adhesion molecules Cell lines Cell surface Cells, Cultured Chemokines Chemokines - immunology Clinical trials Cytokines Cytokines - immunology Endothelial cells Endothelial Cells - drug effects Endothelial Cells - immunology Glucose transporter Hepatocytes Human Umbilical Vein Endothelial Cells Humanities and Social Sciences Humans Inflammation Inhibitors Interleukin 6 Interleukin-1beta - antagonists & inhibitors Interleukin-1beta - immunology JNK protein Kinases Mice Monocyte chemoattractant protein Monocyte chemoattractant protein 1 Monocytes mRNA multidisciplinary Phosphorylation Proteins Reabsorption Science Science (multidisciplinary) Sodium Sodium-Glucose Transporter 2 Inhibitors - pharmacology Transcription factors |
title | Canagliflozin inhibits interleukin-1β-stimulated cytokine and chemokine secretion in vascular endothelial cells by AMP-activated protein kinase-dependent and -independent mechanisms |
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