Caveolin-1 is a critical determinant of autophagy, metabolic switching, and oxidative stress in vascular endothelium
Caveolin-1 is a scaffolding/regulatory protein that interacts with diverse signaling molecules. Caveolin-1(null) mice have marked metabolic abnormalities, yet the underlying molecular mechanisms are incompletely understood. We found the redox stress plasma biomarker plasma 8-isoprostane was elevated...
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| creator | Shiroto, Takashi Romero, Natalia Sugiyama, Toru Sartoretto, Juliano L Kalwa, Hermann Yan, Zhonghua Shimokawa, Hiroaki Michel, Thomas |
| description | Caveolin-1 is a scaffolding/regulatory protein that interacts with diverse signaling molecules. Caveolin-1(null) mice have marked metabolic abnormalities, yet the underlying molecular mechanisms are incompletely understood. We found the redox stress plasma biomarker plasma 8-isoprostane was elevated in caveolin-1(null) mice, and discovered that siRNA-mediated caveolin-1 knockdown in endothelial cells promoted significant increases in intracellular H₂O₂. Mitochondrial ROS production was increased in endothelial cells after caveolin-1 knockdown; 2-deoxy-D-glucose attenuated this increase, implicating caveolin-1 in control of glycolytic pathways. We performed unbiased metabolomic characterizations of endothelial cell lysates following caveolin-1 knockdown, and discovered strikingly increased levels (up to 30-fold) of cellular dipeptides, consistent with autophagy activation. Metabolomic analyses revealed that caveolin-1 knockdown led to a decrease in glycolytic intermediates, accompanied by an increase in fatty acids, suggesting a metabolic switch. Taken together, these results establish that caveolin-1 plays a central role in regulation of oxidative stress, metabolic switching, and autophagy in the endothelium, and may represent a critical target in cardiovascular diseases. |
| doi_str_mv | 10.1371/journal.pone.0087871 |
| format | Article |
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Caveolin-1(null) mice have marked metabolic abnormalities, yet the underlying molecular mechanisms are incompletely understood. We found the redox stress plasma biomarker plasma 8-isoprostane was elevated in caveolin-1(null) mice, and discovered that siRNA-mediated caveolin-1 knockdown in endothelial cells promoted significant increases in intracellular H₂O₂. Mitochondrial ROS production was increased in endothelial cells after caveolin-1 knockdown; 2-deoxy-D-glucose attenuated this increase, implicating caveolin-1 in control of glycolytic pathways. We performed unbiased metabolomic characterizations of endothelial cell lysates following caveolin-1 knockdown, and discovered strikingly increased levels (up to 30-fold) of cellular dipeptides, consistent with autophagy activation. Metabolomic analyses revealed that caveolin-1 knockdown led to a decrease in glycolytic intermediates, accompanied by an increase in fatty acids, suggesting a metabolic switch. Taken together, these results establish that caveolin-1 plays a central role in regulation of oxidative stress, metabolic switching, and autophagy in the endothelium, and may represent a critical target in cardiovascular diseases.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0087871</identifier><identifier>PMID: 24498385</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Abnormalities ; Animals ; Aorta - metabolism ; Aorta - pathology ; Autophagy ; Bioindicators ; Biology ; Biomarkers ; Cancer ; Cardiovascular diseases ; Catalase - metabolism ; Cattle ; Caveolin ; Caveolin 1 - antagonists & inhibitors ; Caveolin 1 - physiology ; Caveolin-1 ; Cell culture ; Cell death ; Cells, Cultured ; Endothelial cells ; Endothelium ; Endothelium, Vascular - metabolism ; Endothelium, Vascular - pathology ; Experiments ; Fatty acids ; Fibroblasts ; Glucose ; Glutathione - metabolism ; Glycolysis ; Heart diseases ; Homeostasis ; Hospitals ; Hydrogen peroxide ; Hydrogen Peroxide - metabolism ; Hypertension ; Insulin resistance ; Intermediates ; Kinases ; Laboratories ; Life sciences ; Lysates ; Medical schools ; Medicine ; Metabolism ; Metabolome ; Metabolomics ; Mice ; Mice, Knockout ; Mitochondria ; Mitochondria - metabolism ; Mitochondria - pathology ; Molecular modelling ; Nitric oxide ; Oxidative Stress ; Phagocytosis ; Physiology ; Proteins ; Reactive Oxygen Species - metabolism ; RNA, Small Interfering - genetics ; Rodents ; Scaffolding ; Signal Transduction ; Signaling ; siRNA ; Switching</subject><ispartof>PloS one, 2014-02, Vol.9 (2), p.e87871</ispartof><rights>COPYRIGHT 2014 Public Library of Science</rights><rights>2014 Shiroto 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. 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Caveolin-1(null) mice have marked metabolic abnormalities, yet the underlying molecular mechanisms are incompletely understood. We found the redox stress plasma biomarker plasma 8-isoprostane was elevated in caveolin-1(null) mice, and discovered that siRNA-mediated caveolin-1 knockdown in endothelial cells promoted significant increases in intracellular H₂O₂. Mitochondrial ROS production was increased in endothelial cells after caveolin-1 knockdown; 2-deoxy-D-glucose attenuated this increase, implicating caveolin-1 in control of glycolytic pathways. We performed unbiased metabolomic characterizations of endothelial cell lysates following caveolin-1 knockdown, and discovered strikingly increased levels (up to 30-fold) of cellular dipeptides, consistent with autophagy activation. Metabolomic analyses revealed that caveolin-1 knockdown led to a decrease in glycolytic intermediates, accompanied by an increase in fatty acids, suggesting a metabolic switch. Taken together, these results establish that caveolin-1 plays a central role in regulation of oxidative stress, metabolic switching, and autophagy in the endothelium, and may represent a critical target in cardiovascular diseases.</description><subject>Abnormalities</subject><subject>Animals</subject><subject>Aorta - metabolism</subject><subject>Aorta - pathology</subject><subject>Autophagy</subject><subject>Bioindicators</subject><subject>Biology</subject><subject>Biomarkers</subject><subject>Cancer</subject><subject>Cardiovascular diseases</subject><subject>Catalase - metabolism</subject><subject>Cattle</subject><subject>Caveolin</subject><subject>Caveolin 1 - antagonists & inhibitors</subject><subject>Caveolin 1 - physiology</subject><subject>Caveolin-1</subject><subject>Cell culture</subject><subject>Cell death</subject><subject>Cells, Cultured</subject><subject>Endothelial cells</subject><subject>Endothelium</subject><subject>Endothelium, Vascular - metabolism</subject><subject>Endothelium, Vascular - pathology</subject><subject>Experiments</subject><subject>Fatty acids</subject><subject>Fibroblasts</subject><subject>Glucose</subject><subject>Glutathione - metabolism</subject><subject>Glycolysis</subject><subject>Heart diseases</subject><subject>Homeostasis</subject><subject>Hospitals</subject><subject>Hydrogen peroxide</subject><subject>Hydrogen Peroxide - metabolism</subject><subject>Hypertension</subject><subject>Insulin resistance</subject><subject>Intermediates</subject><subject>Kinases</subject><subject>Laboratories</subject><subject>Life sciences</subject><subject>Lysates</subject><subject>Medical schools</subject><subject>Medicine</subject><subject>Metabolism</subject><subject>Metabolome</subject><subject>Metabolomics</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>Mitochondria</subject><subject>Mitochondria - metabolism</subject><subject>Mitochondria - pathology</subject><subject>Molecular modelling</subject><subject>Nitric oxide</subject><subject>Oxidative Stress</subject><subject>Phagocytosis</subject><subject>Physiology</subject><subject>Proteins</subject><subject>Reactive Oxygen Species - metabolism</subject><subject>RNA, Small Interfering - genetics</subject><subject>Rodents</subject><subject>Scaffolding</subject><subject>Signal Transduction</subject><subject>Signaling</subject><subject>siRNA</subject><subject>Switching</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNqNkm1rFDEUhQdRbK3-A9GAIAjdNZnMS_JFKIsvhULBt6_hTuZmN8tMsk0ya_vvTd1t6YKC5EPCzXNOwuEUxUtG54y37P3aT8HBMN94h3NKRSta9qg4ZpKXs6ak_PGD81HxLMY1pTUXTfO0OCqrSgou6uMiLWCLfrBuxoiNBIgONlkNA-kxYRitA5eINwSm5DcrWN6ckhETdFmjSfxlk15Ztzwl4Hrir20PyW6RxBQwRmId2ULU0wCBoOt9WuFgp_F58cTAEPHFfj8pfnz6-H3xZXZx-fl8cXYx020t0gwMrWWDWkojjATacda1nELbNVjXphHA2waE0abqOsnaEoUsS9pUXWmg7ik_KV7vfDeDj2ofWFSskhWtW0FZJs53RO9hrTbBjhBulAer_gx8WCoIOY8BFbJemrI3FYi6QtaAQVYjtD3vsZFGZ68P-9embsReo0sBhgPTwxtnV2rpt4pLVrJSZoM3e4PgryaM6R9f3lNLyL-yzvhspkcbtTqrWiE4k2WVqflfqLx6HK3OlTE2zw8E7w4EmUl4nZYwxajOv339f_by5yH79gG7QhjSKvphSta7eAhWO1AHH2NAc58co-q28XdpqNvGq33js-zVw9TvRXcV578BXsn-OQ</recordid><startdate>20140203</startdate><enddate>20140203</enddate><creator>Shiroto, Takashi</creator><creator>Romero, Natalia</creator><creator>Sugiyama, Toru</creator><creator>Sartoretto, Juliano L</creator><creator>Kalwa, Hermann</creator><creator>Yan, Zhonghua</creator><creator>Shimokawa, Hiroaki</creator><creator>Michel, Thomas</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>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20140203</creationdate><title>Caveolin-1 is a critical determinant of autophagy, metabolic switching, and oxidative stress in vascular endothelium</title><author>Shiroto, Takashi ; Romero, Natalia ; Sugiyama, Toru ; Sartoretto, Juliano L ; Kalwa, Hermann ; Yan, Zhonghua ; Shimokawa, Hiroaki ; Michel, Thomas</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c758t-af0596ec99f8f9a0b31b730a7b6e55f68a376a8fcf4bb9172e8922064b2fa5d03</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Abnormalities</topic><topic>Animals</topic><topic>Aorta - 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Caveolin-1(null) mice have marked metabolic abnormalities, yet the underlying molecular mechanisms are incompletely understood. We found the redox stress plasma biomarker plasma 8-isoprostane was elevated in caveolin-1(null) mice, and discovered that siRNA-mediated caveolin-1 knockdown in endothelial cells promoted significant increases in intracellular H₂O₂. Mitochondrial ROS production was increased in endothelial cells after caveolin-1 knockdown; 2-deoxy-D-glucose attenuated this increase, implicating caveolin-1 in control of glycolytic pathways. We performed unbiased metabolomic characterizations of endothelial cell lysates following caveolin-1 knockdown, and discovered strikingly increased levels (up to 30-fold) of cellular dipeptides, consistent with autophagy activation. Metabolomic analyses revealed that caveolin-1 knockdown led to a decrease in glycolytic intermediates, accompanied by an increase in fatty acids, suggesting a metabolic switch. Taken together, these results establish that caveolin-1 plays a central role in regulation of oxidative stress, metabolic switching, and autophagy in the endothelium, and may represent a critical target in cardiovascular diseases.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>24498385</pmid><doi>10.1371/journal.pone.0087871</doi><tpages>e87871</tpages><oa>free_for_read</oa></addata></record> |
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| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2014-02, Vol.9 (2), p.e87871 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1494057801 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Free Full-Text Journals in Chemistry; Public Library of Science (PLoS) |
| subjects | Abnormalities Animals Aorta - metabolism Aorta - pathology Autophagy Bioindicators Biology Biomarkers Cancer Cardiovascular diseases Catalase - metabolism Cattle Caveolin Caveolin 1 - antagonists & inhibitors Caveolin 1 - physiology Caveolin-1 Cell culture Cell death Cells, Cultured Endothelial cells Endothelium Endothelium, Vascular - metabolism Endothelium, Vascular - pathology Experiments Fatty acids Fibroblasts Glucose Glutathione - metabolism Glycolysis Heart diseases Homeostasis Hospitals Hydrogen peroxide Hydrogen Peroxide - metabolism Hypertension Insulin resistance Intermediates Kinases Laboratories Life sciences Lysates Medical schools Medicine Metabolism Metabolome Metabolomics Mice Mice, Knockout Mitochondria Mitochondria - metabolism Mitochondria - pathology Molecular modelling Nitric oxide Oxidative Stress Phagocytosis Physiology Proteins Reactive Oxygen Species - metabolism RNA, Small Interfering - genetics Rodents Scaffolding Signal Transduction Signaling siRNA Switching |
| title | Caveolin-1 is a critical determinant of autophagy, metabolic switching, and oxidative stress in vascular endothelium |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-09T21%3A54%3A33IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Caveolin-1%20is%20a%20critical%20determinant%20of%20autophagy,%20metabolic%20switching,%20and%20oxidative%20stress%20in%20vascular%20endothelium&rft.jtitle=PloS%20one&rft.au=Shiroto,%20Takashi&rft.date=2014-02-03&rft.volume=9&rft.issue=2&rft.spage=e87871&rft.pages=e87871-&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0087871&rft_dat=%3Cgale_plos_%3EA478831924%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1494057801&rft_id=info:pmid/24498385&rft_galeid=A478831924&rft_doaj_id=oai_doaj_org_article_e1d9f2df4a854e16afe15ea7d3de69fc&rfr_iscdi=true |