Activation of neutral sphingomyelinase 2 through hyperglycemia contributes to endothelial apoptosis via vesicle-bound intercellular transfer of ceramides
Background Pro-apoptotic and pro-inflammatory ceramides are crucially involved in atherosclerotic plaque development. Local cellular ceramide accumulation mediates endothelial apoptosis, especially in type 2 diabetes mellitus, which is a major cardiovascular risk factor. In recent years, large extra...
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| Veröffentlicht in: | Cellular and molecular life sciences : CMLS 2022-01, Vol.79 (1), p.48-48, Article 48 |
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| creator | Zietzer, Andreas Jahnel, Alina Lisann Bulic, Marko Gutbrod, Katharina Düsing, Philip Hosen, Mohammed Rabiul Dörmann, Peter Werner, Nikos Nickenig, Georg Jansen, Felix |
| description | Background
Pro-apoptotic and pro-inflammatory ceramides are crucially involved in atherosclerotic plaque development. Local cellular ceramide accumulation mediates endothelial apoptosis, especially in type 2 diabetes mellitus, which is a major cardiovascular risk factor. In recent years, large extracellular vesicles (lEVs) have been identified as an important means of intercellular communication and as regulators of cardiovascular health and disease. A potential role for lEVs as vehicles for ceramide transfer and inductors of diabetes-associated endothelial apoptosis has never been investigated.
Methods and Results
A mass-spectrometric analysis of human coronary artery endothelial cells (HCAECs) and their lEVs revealed C16 ceramide (d18:1–16:0) to be the most abundant ceramide in lEVs and to be significantly increased in lEVs after hyperglycemic injury to HCAECs. The increased packaging of ceramide into lEVs after hyperglycemic injury was shown to be dependent on neutral sphingomyelinase 2 (nSMase2), which was upregulated in glucose-treated HCAECs. lEVs from hyperglycemic HCAECs induced apoptosis in the recipient HCAECs compared to native lEVs from untreated HCAECs. Similarly, lEVs from hyperglycemic mice after streptozotocin injection induced higher rates of apoptosis in murine endothelial cells compared to lEVs from normoglycemic mice. To generate lEVs with high levels of C16 ceramide, ceramide was applied exogenously and shown to be effectively packaged into the lEVs, which then induced apoptosis in lEV-recipient HCAECs via activation of caspase 3. Intercellular transfer of ceramide through lEVs was confirmed by use of a fluorescently labeled ceramide analogue. Treatment of HCAECs with a pharmacological inhibitor of nSMases (GW4869) or siRNA-mediated downregulation of nSMase2 abrogated the glucose-mediated effect on apoptosis in lEV-recipient cells. In contrast, for small EVs (sEVs), hyperglycemic injury or GW4869 treatment had no effect on apoptosis induction in sEV-recipient cells.
Conclusion
lEVs mediate the induction of apoptosis in endothelial cells in response to hyperglycemic injury through intercellular transfer of ceramides.
Graphical abstract |
| doi_str_mv | 10.1007/s00018-021-04049-5 |
| format | Article |
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Pro-apoptotic and pro-inflammatory ceramides are crucially involved in atherosclerotic plaque development. Local cellular ceramide accumulation mediates endothelial apoptosis, especially in type 2 diabetes mellitus, which is a major cardiovascular risk factor. In recent years, large extracellular vesicles (lEVs) have been identified as an important means of intercellular communication and as regulators of cardiovascular health and disease. A potential role for lEVs as vehicles for ceramide transfer and inductors of diabetes-associated endothelial apoptosis has never been investigated.
Methods and Results
A mass-spectrometric analysis of human coronary artery endothelial cells (HCAECs) and their lEVs revealed C16 ceramide (d18:1–16:0) to be the most abundant ceramide in lEVs and to be significantly increased in lEVs after hyperglycemic injury to HCAECs. The increased packaging of ceramide into lEVs after hyperglycemic injury was shown to be dependent on neutral sphingomyelinase 2 (nSMase2), which was upregulated in glucose-treated HCAECs. lEVs from hyperglycemic HCAECs induced apoptosis in the recipient HCAECs compared to native lEVs from untreated HCAECs. Similarly, lEVs from hyperglycemic mice after streptozotocin injection induced higher rates of apoptosis in murine endothelial cells compared to lEVs from normoglycemic mice. To generate lEVs with high levels of C16 ceramide, ceramide was applied exogenously and shown to be effectively packaged into the lEVs, which then induced apoptosis in lEV-recipient HCAECs via activation of caspase 3. Intercellular transfer of ceramide through lEVs was confirmed by use of a fluorescently labeled ceramide analogue. Treatment of HCAECs with a pharmacological inhibitor of nSMases (GW4869) or siRNA-mediated downregulation of nSMase2 abrogated the glucose-mediated effect on apoptosis in lEV-recipient cells. In contrast, for small EVs (sEVs), hyperglycemic injury or GW4869 treatment had no effect on apoptosis induction in sEV-recipient cells.
Conclusion
lEVs mediate the induction of apoptosis in endothelial cells in response to hyperglycemic injury through intercellular transfer of ceramides.
Graphical abstract</description><identifier>ISSN: 1420-682X</identifier><identifier>EISSN: 1420-9071</identifier><identifier>DOI: 10.1007/s00018-021-04049-5</identifier><identifier>PMID: 34951654</identifier><language>eng</language><publisher>Cham: Springer International Publishing</publisher><subject>Animals ; Apoptosis ; Arteriosclerosis ; Atherosclerosis ; Biochemistry ; Biomedical and Life Sciences ; Biomedicine ; Cardiovascular diseases ; Carotid Artery Diseases - metabolism ; Caspase-3 ; Cell Biology ; Cell Line ; Ceramide ; Ceramides - metabolism ; Coronary artery ; Diabetes ; Diabetes mellitus ; Diabetes mellitus (non-insulin dependent) ; Diabetes Mellitus, Type 2 - metabolism ; Endothelial Cells ; Extracellular vesicles ; Extracellular Vesicles - metabolism ; Glucose ; Health risks ; Humans ; Hyperglycemia ; Inductors ; Inflammation ; Injuries ; Life Sciences ; Male ; Mice ; Mice, Inbred C57BL ; Original ; Original Article ; Risk analysis ; Risk factors ; siRNA ; Spectrometry ; Sphingomyelin phosphodiesterase ; Sphingomyelin Phosphodiesterase - physiology ; Streptozocin</subject><ispartof>Cellular and molecular life sciences : CMLS, 2022-01, Vol.79 (1), p.48-48, Article 48</ispartof><rights>The Author(s) 2021</rights><rights>2021. The Author(s).</rights><rights>The Author(s) 2021. 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-991943e2f103d4ae862803808c18d27677e2a06e342ed2f4808bb5836dad38393</citedby><cites>FETCH-LOGICAL-c474t-991943e2f103d4ae862803808c18d27677e2a06e342ed2f4808bb5836dad38393</cites><orcidid>0000-0001-5759-7627</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/PMC8739297/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8739297/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,41464,42533,51294,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34951654$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Zietzer, Andreas</creatorcontrib><creatorcontrib>Jahnel, Alina Lisann</creatorcontrib><creatorcontrib>Bulic, Marko</creatorcontrib><creatorcontrib>Gutbrod, Katharina</creatorcontrib><creatorcontrib>Düsing, Philip</creatorcontrib><creatorcontrib>Hosen, Mohammed Rabiul</creatorcontrib><creatorcontrib>Dörmann, Peter</creatorcontrib><creatorcontrib>Werner, Nikos</creatorcontrib><creatorcontrib>Nickenig, Georg</creatorcontrib><creatorcontrib>Jansen, Felix</creatorcontrib><title>Activation of neutral sphingomyelinase 2 through hyperglycemia contributes to endothelial apoptosis via vesicle-bound intercellular transfer of ceramides</title><title>Cellular and molecular life sciences : CMLS</title><addtitle>Cell. Mol. Life Sci</addtitle><addtitle>Cell Mol Life Sci</addtitle><description>Background
Pro-apoptotic and pro-inflammatory ceramides are crucially involved in atherosclerotic plaque development. Local cellular ceramide accumulation mediates endothelial apoptosis, especially in type 2 diabetes mellitus, which is a major cardiovascular risk factor. In recent years, large extracellular vesicles (lEVs) have been identified as an important means of intercellular communication and as regulators of cardiovascular health and disease. A potential role for lEVs as vehicles for ceramide transfer and inductors of diabetes-associated endothelial apoptosis has never been investigated.
Methods and Results
A mass-spectrometric analysis of human coronary artery endothelial cells (HCAECs) and their lEVs revealed C16 ceramide (d18:1–16:0) to be the most abundant ceramide in lEVs and to be significantly increased in lEVs after hyperglycemic injury to HCAECs. The increased packaging of ceramide into lEVs after hyperglycemic injury was shown to be dependent on neutral sphingomyelinase 2 (nSMase2), which was upregulated in glucose-treated HCAECs. lEVs from hyperglycemic HCAECs induced apoptosis in the recipient HCAECs compared to native lEVs from untreated HCAECs. Similarly, lEVs from hyperglycemic mice after streptozotocin injection induced higher rates of apoptosis in murine endothelial cells compared to lEVs from normoglycemic mice. To generate lEVs with high levels of C16 ceramide, ceramide was applied exogenously and shown to be effectively packaged into the lEVs, which then induced apoptosis in lEV-recipient HCAECs via activation of caspase 3. Intercellular transfer of ceramide through lEVs was confirmed by use of a fluorescently labeled ceramide analogue. Treatment of HCAECs with a pharmacological inhibitor of nSMases (GW4869) or siRNA-mediated downregulation of nSMase2 abrogated the glucose-mediated effect on apoptosis in lEV-recipient cells. In contrast, for small EVs (sEVs), hyperglycemic injury or GW4869 treatment had no effect on apoptosis induction in sEV-recipient cells.
Conclusion
lEVs mediate the induction of apoptosis in endothelial cells in response to hyperglycemic injury through intercellular transfer of ceramides.
Graphical abstract</description><subject>Animals</subject><subject>Apoptosis</subject><subject>Arteriosclerosis</subject><subject>Atherosclerosis</subject><subject>Biochemistry</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Cardiovascular diseases</subject><subject>Carotid Artery Diseases - metabolism</subject><subject>Caspase-3</subject><subject>Cell Biology</subject><subject>Cell Line</subject><subject>Ceramide</subject><subject>Ceramides - metabolism</subject><subject>Coronary artery</subject><subject>Diabetes</subject><subject>Diabetes mellitus</subject><subject>Diabetes mellitus (non-insulin dependent)</subject><subject>Diabetes Mellitus, Type 2 - metabolism</subject><subject>Endothelial Cells</subject><subject>Extracellular vesicles</subject><subject>Extracellular Vesicles - metabolism</subject><subject>Glucose</subject><subject>Health risks</subject><subject>Humans</subject><subject>Hyperglycemia</subject><subject>Inductors</subject><subject>Inflammation</subject><subject>Injuries</subject><subject>Life Sciences</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Original</subject><subject>Original Article</subject><subject>Risk analysis</subject><subject>Risk factors</subject><subject>siRNA</subject><subject>Spectrometry</subject><subject>Sphingomyelin phosphodiesterase</subject><subject>Sphingomyelin Phosphodiesterase - 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Andreas</creator><creator>Jahnel, Alina Lisann</creator><creator>Bulic, Marko</creator><creator>Gutbrod, Katharina</creator><creator>Düsing, Philip</creator><creator>Hosen, Mohammed Rabiul</creator><creator>Dörmann, Peter</creator><creator>Werner, Nikos</creator><creator>Nickenig, Georg</creator><creator>Jansen, Felix</creator><general>Springer International Publishing</general><general>Springer Nature 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of neutral sphingomyelinase 2 through hyperglycemia contributes to endothelial apoptosis via vesicle-bound intercellular transfer of ceramides</title><author>Zietzer, Andreas ; Jahnel, Alina Lisann ; Bulic, Marko ; Gutbrod, Katharina ; Düsing, Philip ; Hosen, Mohammed Rabiul ; Dörmann, Peter ; Werner, Nikos ; Nickenig, Georg ; Jansen, Felix</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c474t-991943e2f103d4ae862803808c18d27677e2a06e342ed2f4808bb5836dad38393</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Animals</topic><topic>Apoptosis</topic><topic>Arteriosclerosis</topic><topic>Atherosclerosis</topic><topic>Biochemistry</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>Cardiovascular diseases</topic><topic>Carotid Artery Diseases - metabolism</topic><topic>Caspase-3</topic><topic>Cell Biology</topic><topic>Cell Line</topic><topic>Ceramide</topic><topic>Ceramides - metabolism</topic><topic>Coronary artery</topic><topic>Diabetes</topic><topic>Diabetes mellitus</topic><topic>Diabetes mellitus (non-insulin dependent)</topic><topic>Diabetes Mellitus, Type 2 - metabolism</topic><topic>Endothelial Cells</topic><topic>Extracellular vesicles</topic><topic>Extracellular Vesicles - metabolism</topic><topic>Glucose</topic><topic>Health risks</topic><topic>Humans</topic><topic>Hyperglycemia</topic><topic>Inductors</topic><topic>Inflammation</topic><topic>Injuries</topic><topic>Life Sciences</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Original</topic><topic>Original Article</topic><topic>Risk analysis</topic><topic>Risk factors</topic><topic>siRNA</topic><topic>Spectrometry</topic><topic>Sphingomyelin phosphodiesterase</topic><topic>Sphingomyelin Phosphodiesterase - 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through hyperglycemia contributes to endothelial apoptosis via vesicle-bound intercellular transfer of ceramides</atitle><jtitle>Cellular and molecular life sciences : CMLS</jtitle><stitle>Cell. Mol. Life Sci</stitle><addtitle>Cell Mol Life Sci</addtitle><date>2022-01-01</date><risdate>2022</risdate><volume>79</volume><issue>1</issue><spage>48</spage><epage>48</epage><pages>48-48</pages><artnum>48</artnum><issn>1420-682X</issn><eissn>1420-9071</eissn><abstract>Background
Pro-apoptotic and pro-inflammatory ceramides are crucially involved in atherosclerotic plaque development. Local cellular ceramide accumulation mediates endothelial apoptosis, especially in type 2 diabetes mellitus, which is a major cardiovascular risk factor. In recent years, large extracellular vesicles (lEVs) have been identified as an important means of intercellular communication and as regulators of cardiovascular health and disease. A potential role for lEVs as vehicles for ceramide transfer and inductors of diabetes-associated endothelial apoptosis has never been investigated.
Methods and Results
A mass-spectrometric analysis of human coronary artery endothelial cells (HCAECs) and their lEVs revealed C16 ceramide (d18:1–16:0) to be the most abundant ceramide in lEVs and to be significantly increased in lEVs after hyperglycemic injury to HCAECs. The increased packaging of ceramide into lEVs after hyperglycemic injury was shown to be dependent on neutral sphingomyelinase 2 (nSMase2), which was upregulated in glucose-treated HCAECs. lEVs from hyperglycemic HCAECs induced apoptosis in the recipient HCAECs compared to native lEVs from untreated HCAECs. Similarly, lEVs from hyperglycemic mice after streptozotocin injection induced higher rates of apoptosis in murine endothelial cells compared to lEVs from normoglycemic mice. To generate lEVs with high levels of C16 ceramide, ceramide was applied exogenously and shown to be effectively packaged into the lEVs, which then induced apoptosis in lEV-recipient HCAECs via activation of caspase 3. Intercellular transfer of ceramide through lEVs was confirmed by use of a fluorescently labeled ceramide analogue. Treatment of HCAECs with a pharmacological inhibitor of nSMases (GW4869) or siRNA-mediated downregulation of nSMase2 abrogated the glucose-mediated effect on apoptosis in lEV-recipient cells. In contrast, for small EVs (sEVs), hyperglycemic injury or GW4869 treatment had no effect on apoptosis induction in sEV-recipient cells.
Conclusion
lEVs mediate the induction of apoptosis in endothelial cells in response to hyperglycemic injury through intercellular transfer of ceramides.
Graphical abstract</abstract><cop>Cham</cop><pub>Springer International Publishing</pub><pmid>34951654</pmid><doi>10.1007/s00018-021-04049-5</doi><tpages>1</tpages><orcidid>https://orcid.org/0000-0001-5759-7627</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | Cellular and molecular life sciences : CMLS, 2022-01, Vol.79 (1), p.48-48, Article 48 |
| issn | 1420-682X 1420-9071 |
| language | eng |
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| source | MEDLINE; SpringerLink Journals; PubMed Central |
| subjects | Animals Apoptosis Arteriosclerosis Atherosclerosis Biochemistry Biomedical and Life Sciences Biomedicine Cardiovascular diseases Carotid Artery Diseases - metabolism Caspase-3 Cell Biology Cell Line Ceramide Ceramides - metabolism Coronary artery Diabetes Diabetes mellitus Diabetes mellitus (non-insulin dependent) Diabetes Mellitus, Type 2 - metabolism Endothelial Cells Extracellular vesicles Extracellular Vesicles - metabolism Glucose Health risks Humans Hyperglycemia Inductors Inflammation Injuries Life Sciences Male Mice Mice, Inbred C57BL Original Original Article Risk analysis Risk factors siRNA Spectrometry Sphingomyelin phosphodiesterase Sphingomyelin Phosphodiesterase - physiology Streptozocin |
| title | Activation of neutral sphingomyelinase 2 through hyperglycemia contributes to endothelial apoptosis via vesicle-bound intercellular transfer of ceramides |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-09T22%3A27%3A34IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Activation%20of%20neutral%20sphingomyelinase%202%20through%20hyperglycemia%20contributes%20to%20endothelial%20apoptosis%20via%20vesicle-bound%20intercellular%20transfer%20of%20ceramides&rft.jtitle=Cellular%20and%20molecular%20life%20sciences%20:%20CMLS&rft.au=Zietzer,%20Andreas&rft.date=2022-01-01&rft.volume=79&rft.issue=1&rft.spage=48&rft.epage=48&rft.pages=48-48&rft.artnum=48&rft.issn=1420-682X&rft.eissn=1420-9071&rft_id=info:doi/10.1007/s00018-021-04049-5&rft_dat=%3Cproquest_pubme%3E2614225648%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2617110909&rft_id=info:pmid/34951654&rfr_iscdi=true |