Hyperglycemia Promotes Endothelial Cell Senescence through AQR/PLAU Signaling Axis
Hyperglycemia is reported to accelerate endothelial cell senescence that contributes to diabetic complications. The underlying mechanism, however, remains elusive. We previously demonstrated as a susceptibility gene for type 2 diabetes mellitus (T2DM) and showed that it was increased in multiple tis...
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| Veröffentlicht in: | International journal of molecular sciences 2022-03, Vol.23 (5), p.2879 |
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| creator | Wan, Yiqi Liu, Zhirui Wu, Andong Khan, Abdul Haseeb Zhu, Ying Ding, Shuangjin Li, Xueer Zhao, Ya Dai, Ximo Zhou, Jin Liu, Jiankun Li, Yuanyuan Gong, Xueting Liu, Man Tian, Xiao-Li |
| description | Hyperglycemia is reported to accelerate endothelial cell senescence that contributes to diabetic complications. The underlying mechanism, however, remains elusive. We previously demonstrated
as a susceptibility gene for type 2 diabetes mellitus (T2DM) and showed that it was increased in multiple tissues in models with T2DM or metabolic syndrome. This study aimed to investigate the role of AQR in hyperglycemia-induced senescence and its underlying mechanism. Here, we retrieved several datasets of the aging models and found the expression of AQR was increased by high glucose and by aging across species, including
(whole-body), rat (cardiac tissues), and monkey (blood). we validated the increased AQR expression in senescent human umbilical vein endothelial cells (HUVECs). When overexpressed, AQR promoted the endothelial cell senescence, confirmed by an increased number of cells stained with senescence-associated beta-galactosidase and upregulation of CDKN1A (P21) as well as the prohibited cellular colony formation and G2/M phase arrest. To explore the mechanism by which AQR regulated the cellular senescence, transcriptomic analyses of HUVECs with the overexpression and knockdown of the AQR were performed. We identified 52 co-expressed genes that were enriched, in the terms of plasminogen activation, innate immunity, immunity, and antiviral defense. Among co-expressed genes,
was selected to evaluate its contribution to senescence for its highest strength in the enrichment of the biological process. We demonstrated that the knockdown of PLAU rescued senescence-related phenotypes, endothelial cell activation, and inflammation in models induced by AQR or TNF-α. These findings, for the first time, indicate that AQR/PLAU is a critical signaling axis in the modulation of endothelial cell senescence, revealing a novel link between hyperglycemia and vascular dysfunction. The study may have implications in the prevention of premature vascular aging associated with T2DM. |
| doi_str_mv | 10.3390/ijms23052879 |
| format | Article |
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as a susceptibility gene for type 2 diabetes mellitus (T2DM) and showed that it was increased in multiple tissues in models with T2DM or metabolic syndrome. This study aimed to investigate the role of AQR in hyperglycemia-induced senescence and its underlying mechanism. Here, we retrieved several datasets of the aging models and found the expression of AQR was increased by high glucose and by aging across species, including
(whole-body), rat (cardiac tissues), and monkey (blood). we validated the increased AQR expression in senescent human umbilical vein endothelial cells (HUVECs). When overexpressed, AQR promoted the endothelial cell senescence, confirmed by an increased number of cells stained with senescence-associated beta-galactosidase and upregulation of CDKN1A (P21) as well as the prohibited cellular colony formation and G2/M phase arrest. To explore the mechanism by which AQR regulated the cellular senescence, transcriptomic analyses of HUVECs with the overexpression and knockdown of the AQR were performed. We identified 52 co-expressed genes that were enriched, in the terms of plasminogen activation, innate immunity, immunity, and antiviral defense. Among co-expressed genes,
was selected to evaluate its contribution to senescence for its highest strength in the enrichment of the biological process. We demonstrated that the knockdown of PLAU rescued senescence-related phenotypes, endothelial cell activation, and inflammation in models induced by AQR or TNF-α. These findings, for the first time, indicate that AQR/PLAU is a critical signaling axis in the modulation of endothelial cell senescence, revealing a novel link between hyperglycemia and vascular dysfunction. The study may have implications in the prevention of premature vascular aging associated with T2DM.</description><identifier>ISSN: 1422-0067</identifier><identifier>ISSN: 1661-6596</identifier><identifier>EISSN: 1422-0067</identifier><identifier>DOI: 10.3390/ijms23052879</identifier><identifier>PMID: 35270021</identifier><language>eng</language><publisher>Switzerland: MDPI AG</publisher><subject>Aging ; Animals ; Biological activity ; Biological Phenomena ; Caenorhabditis elegans ; Cardiovascular disease ; Cell activation ; Cell cycle ; Cell growth ; Cells, Cultured ; Cellular Senescence - genetics ; Datasets ; Diabetes ; Diabetes mellitus ; Diabetes mellitus (non-insulin dependent) ; Diabetes Mellitus, Type 2 ; Endothelial cells ; Galactosidase ; Genes ; Glucose ; Human Umbilical Vein Endothelial Cells - metabolism ; Humans ; Hyperglycemia ; Hyperglycemia - genetics ; Hyperglycemia - metabolism ; Innate immunity ; Metabolic disorders ; Metabolic syndrome ; Phenotypes ; Proteins ; Rats ; Senescence ; Smooth muscle ; Transcriptomics ; Tumor necrosis factor-α ; Umbilical vein ; β-Galactosidase</subject><ispartof>International journal of molecular sciences, 2022-03, Vol.23 (5), p.2879</ispartof><rights>2022 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 (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2022 by the authors. 2022</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c412t-4fc4f43b7d43cad4a17e2988731eedfe1ba647bafdd29d080749e7fbf77a4f143</citedby><cites>FETCH-LOGICAL-c412t-4fc4f43b7d43cad4a17e2988731eedfe1ba647bafdd29d080749e7fbf77a4f143</cites><orcidid>0000-0002-0868-7025 ; 0000-0003-4845-7774 ; 0000-0003-4259-5201</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/PMC8911151/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8911151/$$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/35270021$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Wan, Yiqi</creatorcontrib><creatorcontrib>Liu, Zhirui</creatorcontrib><creatorcontrib>Wu, Andong</creatorcontrib><creatorcontrib>Khan, Abdul Haseeb</creatorcontrib><creatorcontrib>Zhu, Ying</creatorcontrib><creatorcontrib>Ding, Shuangjin</creatorcontrib><creatorcontrib>Li, Xueer</creatorcontrib><creatorcontrib>Zhao, Ya</creatorcontrib><creatorcontrib>Dai, Ximo</creatorcontrib><creatorcontrib>Zhou, Jin</creatorcontrib><creatorcontrib>Liu, Jiankun</creatorcontrib><creatorcontrib>Li, Yuanyuan</creatorcontrib><creatorcontrib>Gong, Xueting</creatorcontrib><creatorcontrib>Liu, Man</creatorcontrib><creatorcontrib>Tian, Xiao-Li</creatorcontrib><title>Hyperglycemia Promotes Endothelial Cell Senescence through AQR/PLAU Signaling Axis</title><title>International journal of molecular sciences</title><addtitle>Int J Mol Sci</addtitle><description>Hyperglycemia is reported to accelerate endothelial cell senescence that contributes to diabetic complications. The underlying mechanism, however, remains elusive. We previously demonstrated
as a susceptibility gene for type 2 diabetes mellitus (T2DM) and showed that it was increased in multiple tissues in models with T2DM or metabolic syndrome. This study aimed to investigate the role of AQR in hyperglycemia-induced senescence and its underlying mechanism. Here, we retrieved several datasets of the aging models and found the expression of AQR was increased by high glucose and by aging across species, including
(whole-body), rat (cardiac tissues), and monkey (blood). we validated the increased AQR expression in senescent human umbilical vein endothelial cells (HUVECs). When overexpressed, AQR promoted the endothelial cell senescence, confirmed by an increased number of cells stained with senescence-associated beta-galactosidase and upregulation of CDKN1A (P21) as well as the prohibited cellular colony formation and G2/M phase arrest. To explore the mechanism by which AQR regulated the cellular senescence, transcriptomic analyses of HUVECs with the overexpression and knockdown of the AQR were performed. We identified 52 co-expressed genes that were enriched, in the terms of plasminogen activation, innate immunity, immunity, and antiviral defense. Among co-expressed genes,
was selected to evaluate its contribution to senescence for its highest strength in the enrichment of the biological process. We demonstrated that the knockdown of PLAU rescued senescence-related phenotypes, endothelial cell activation, and inflammation in models induced by AQR or TNF-α. These findings, for the first time, indicate that AQR/PLAU is a critical signaling axis in the modulation of endothelial cell senescence, revealing a novel link between hyperglycemia and vascular dysfunction. The study may have implications in the prevention of premature vascular aging associated with T2DM.</description><subject>Aging</subject><subject>Animals</subject><subject>Biological activity</subject><subject>Biological Phenomena</subject><subject>Caenorhabditis elegans</subject><subject>Cardiovascular disease</subject><subject>Cell activation</subject><subject>Cell cycle</subject><subject>Cell growth</subject><subject>Cells, Cultured</subject><subject>Cellular Senescence - genetics</subject><subject>Datasets</subject><subject>Diabetes</subject><subject>Diabetes mellitus</subject><subject>Diabetes mellitus (non-insulin dependent)</subject><subject>Diabetes Mellitus, Type 2</subject><subject>Endothelial cells</subject><subject>Galactosidase</subject><subject>Genes</subject><subject>Glucose</subject><subject>Human Umbilical Vein Endothelial Cells - metabolism</subject><subject>Humans</subject><subject>Hyperglycemia</subject><subject>Hyperglycemia - genetics</subject><subject>Hyperglycemia - metabolism</subject><subject>Innate immunity</subject><subject>Metabolic disorders</subject><subject>Metabolic syndrome</subject><subject>Phenotypes</subject><subject>Proteins</subject><subject>Rats</subject><subject>Senescence</subject><subject>Smooth muscle</subject><subject>Transcriptomics</subject><subject>Tumor necrosis factor-α</subject><subject>Umbilical vein</subject><subject>β-Galactosidase</subject><issn>1422-0067</issn><issn>1661-6596</issn><issn>1422-0067</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>BENPR</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNpdkc1Lw0AQxRdRbK3ePEvAiwer-9VuchFKqR9QUFt7XjbJbLplk627idj_3mhVqqeZYX483uMhdErwFWMJvjarMlCGBzQWyR7qEk5pH-Oh2N_ZO-gohBXGlNFBcog6bEBFe5Eumt1v1uALu8mgNCp68q50NYRoUuWuXoI1ykZjsDaaQwUhgyqDqF561xTLaPQ8u36ajhbR3BSVsqYqotG7CcfoQCsb4OR79tDidvIyvu9PH-8exqNpP-OE1n2uM645S0XOWaZyrogAmsSxYAQg10BSNeQiVTrPaZLjGAuegNCpFkJxTTjroZut7rpJS8hbb7VXVq69KZXfSKeM_PupzFIW7k3GCSFkQFqBi28B714bCLUsTRvRWlWBa4KkQxYLQgkTLXr-D125xrehvyghOKc4bqnLLZV5F4IH_WuGYPlZltwtq8XPdgP8wj_tsA_dApD6</recordid><startdate>20220307</startdate><enddate>20220307</enddate><creator>Wan, Yiqi</creator><creator>Liu, Zhirui</creator><creator>Wu, Andong</creator><creator>Khan, Abdul Haseeb</creator><creator>Zhu, Ying</creator><creator>Ding, Shuangjin</creator><creator>Li, Xueer</creator><creator>Zhao, Ya</creator><creator>Dai, Ximo</creator><creator>Zhou, Jin</creator><creator>Liu, Jiankun</creator><creator>Li, Yuanyuan</creator><creator>Gong, Xueting</creator><creator>Liu, Man</creator><creator>Tian, Xiao-Li</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>5PM</scope><orcidid>https://orcid.org/0000-0002-0868-7025</orcidid><orcidid>https://orcid.org/0000-0003-4845-7774</orcidid><orcidid>https://orcid.org/0000-0003-4259-5201</orcidid></search><sort><creationdate>20220307</creationdate><title>Hyperglycemia Promotes Endothelial Cell Senescence through AQR/PLAU Signaling Axis</title><author>Wan, Yiqi ; Liu, Zhirui ; Wu, Andong ; Khan, Abdul Haseeb ; Zhu, Ying ; Ding, Shuangjin ; Li, Xueer ; Zhao, Ya ; Dai, Ximo ; Zhou, Jin ; Liu, Jiankun ; Li, Yuanyuan ; Gong, Xueting ; Liu, Man ; Tian, Xiao-Li</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c412t-4fc4f43b7d43cad4a17e2988731eedfe1ba647bafdd29d080749e7fbf77a4f143</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Aging</topic><topic>Animals</topic><topic>Biological activity</topic><topic>Biological Phenomena</topic><topic>Caenorhabditis elegans</topic><topic>Cardiovascular disease</topic><topic>Cell activation</topic><topic>Cell cycle</topic><topic>Cell growth</topic><topic>Cells, Cultured</topic><topic>Cellular Senescence - genetics</topic><topic>Datasets</topic><topic>Diabetes</topic><topic>Diabetes mellitus</topic><topic>Diabetes mellitus (non-insulin dependent)</topic><topic>Diabetes Mellitus, Type 2</topic><topic>Endothelial cells</topic><topic>Galactosidase</topic><topic>Genes</topic><topic>Glucose</topic><topic>Human Umbilical Vein Endothelial Cells - metabolism</topic><topic>Humans</topic><topic>Hyperglycemia</topic><topic>Hyperglycemia - genetics</topic><topic>Hyperglycemia - metabolism</topic><topic>Innate immunity</topic><topic>Metabolic disorders</topic><topic>Metabolic syndrome</topic><topic>Phenotypes</topic><topic>Proteins</topic><topic>Rats</topic><topic>Senescence</topic><topic>Smooth muscle</topic><topic>Transcriptomics</topic><topic>Tumor necrosis factor-α</topic><topic>Umbilical vein</topic><topic>β-Galactosidase</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Wan, Yiqi</creatorcontrib><creatorcontrib>Liu, Zhirui</creatorcontrib><creatorcontrib>Wu, Andong</creatorcontrib><creatorcontrib>Khan, Abdul Haseeb</creatorcontrib><creatorcontrib>Zhu, Ying</creatorcontrib><creatorcontrib>Ding, Shuangjin</creatorcontrib><creatorcontrib>Li, Xueer</creatorcontrib><creatorcontrib>Zhao, Ya</creatorcontrib><creatorcontrib>Dai, Ximo</creatorcontrib><creatorcontrib>Zhou, Jin</creatorcontrib><creatorcontrib>Liu, Jiankun</creatorcontrib><creatorcontrib>Li, Yuanyuan</creatorcontrib><creatorcontrib>Gong, Xueting</creatorcontrib><creatorcontrib>Liu, Man</creatorcontrib><creatorcontrib>Tian, Xiao-Li</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>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>Wan, Yiqi</au><au>Liu, Zhirui</au><au>Wu, Andong</au><au>Khan, Abdul Haseeb</au><au>Zhu, Ying</au><au>Ding, Shuangjin</au><au>Li, Xueer</au><au>Zhao, Ya</au><au>Dai, Ximo</au><au>Zhou, Jin</au><au>Liu, Jiankun</au><au>Li, Yuanyuan</au><au>Gong, Xueting</au><au>Liu, Man</au><au>Tian, Xiao-Li</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Hyperglycemia Promotes Endothelial Cell Senescence through AQR/PLAU Signaling Axis</atitle><jtitle>International journal of molecular sciences</jtitle><addtitle>Int J Mol Sci</addtitle><date>2022-03-07</date><risdate>2022</risdate><volume>23</volume><issue>5</issue><spage>2879</spage><pages>2879-</pages><issn>1422-0067</issn><issn>1661-6596</issn><eissn>1422-0067</eissn><abstract>Hyperglycemia is reported to accelerate endothelial cell senescence that contributes to diabetic complications. The underlying mechanism, however, remains elusive. We previously demonstrated
as a susceptibility gene for type 2 diabetes mellitus (T2DM) and showed that it was increased in multiple tissues in models with T2DM or metabolic syndrome. This study aimed to investigate the role of AQR in hyperglycemia-induced senescence and its underlying mechanism. Here, we retrieved several datasets of the aging models and found the expression of AQR was increased by high glucose and by aging across species, including
(whole-body), rat (cardiac tissues), and monkey (blood). we validated the increased AQR expression in senescent human umbilical vein endothelial cells (HUVECs). When overexpressed, AQR promoted the endothelial cell senescence, confirmed by an increased number of cells stained with senescence-associated beta-galactosidase and upregulation of CDKN1A (P21) as well as the prohibited cellular colony formation and G2/M phase arrest. To explore the mechanism by which AQR regulated the cellular senescence, transcriptomic analyses of HUVECs with the overexpression and knockdown of the AQR were performed. We identified 52 co-expressed genes that were enriched, in the terms of plasminogen activation, innate immunity, immunity, and antiviral defense. Among co-expressed genes,
was selected to evaluate its contribution to senescence for its highest strength in the enrichment of the biological process. We demonstrated that the knockdown of PLAU rescued senescence-related phenotypes, endothelial cell activation, and inflammation in models induced by AQR or TNF-α. These findings, for the first time, indicate that AQR/PLAU is a critical signaling axis in the modulation of endothelial cell senescence, revealing a novel link between hyperglycemia and vascular dysfunction. The study may have implications in the prevention of premature vascular aging associated with T2DM.</abstract><cop>Switzerland</cop><pub>MDPI AG</pub><pmid>35270021</pmid><doi>10.3390/ijms23052879</doi><orcidid>https://orcid.org/0000-0002-0868-7025</orcidid><orcidid>https://orcid.org/0000-0003-4845-7774</orcidid><orcidid>https://orcid.org/0000-0003-4259-5201</orcidid><oa>free_for_read</oa></addata></record> |
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| source | MDPI - Multidisciplinary Digital Publishing Institute; MEDLINE; EZB-FREE-00999 freely available EZB journals; PubMed Central |
| subjects | Aging Animals Biological activity Biological Phenomena Caenorhabditis elegans Cardiovascular disease Cell activation Cell cycle Cell growth Cells, Cultured Cellular Senescence - genetics Datasets Diabetes Diabetes mellitus Diabetes mellitus (non-insulin dependent) Diabetes Mellitus, Type 2 Endothelial cells Galactosidase Genes Glucose Human Umbilical Vein Endothelial Cells - metabolism Humans Hyperglycemia Hyperglycemia - genetics Hyperglycemia - metabolism Innate immunity Metabolic disorders Metabolic syndrome Phenotypes Proteins Rats Senescence Smooth muscle Transcriptomics Tumor necrosis factor-α Umbilical vein β-Galactosidase |
| title | Hyperglycemia Promotes Endothelial Cell Senescence through AQR/PLAU Signaling Axis |
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