EPAS1 Attenuates Atherosclerosis Initiation at Disturbed Flow Sites Through Endothelial Fatty Acid Uptake
BACKGROUND: Atherosclerotic plaques form unevenly due to disturbed blood flow, causing localized endothelial cell (EC) dysfunction. Obesity exacerbates this process, but the underlying molecular mechanisms are unclear. The transcription factor EPAS1 (HIF2A) has regulatory roles in endothelium, but i...
| Autores: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Tipo de recurso: | artículo |
| Fecha de publicación: | 2024 |
| País: | España |
| Institución: | Universitat Autònoma de Barcelona |
| Repositorio: | Dipòsit Digital de Documents de la UAB |
| Idioma: | inglés |
| OAI Identifier: | oai:ddd.uab.cat:309024 |
| Acceso en línea: | https://ddd.uab.cat/record/309024 https://dx.doi.org/urn:doi:10.1161/CIRCRESAHA.123.324054 |
| Access Level: | acceso abierto |
| Palabra clave: | Atherosclerosis Diet, high-fat Endothelial cells Obesity Plaque, atherosclerotic |
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oai:ddd.uab.cat:309024 |
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España |
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| dc.title.none.fl_str_mv |
EPAS1 Attenuates Atherosclerosis Initiation at Disturbed Flow Sites Through Endothelial Fatty Acid Uptake |
| title |
EPAS1 Attenuates Atherosclerosis Initiation at Disturbed Flow Sites Through Endothelial Fatty Acid Uptake |
| spellingShingle |
EPAS1 Attenuates Atherosclerosis Initiation at Disturbed Flow Sites Through Endothelial Fatty Acid Uptake Pirri, D.|||0000-0002-7051-4176 Atherosclerosis Diet, high-fat Endothelial cells Obesity Plaque, atherosclerotic |
| title_short |
EPAS1 Attenuates Atherosclerosis Initiation at Disturbed Flow Sites Through Endothelial Fatty Acid Uptake |
| title_full |
EPAS1 Attenuates Atherosclerosis Initiation at Disturbed Flow Sites Through Endothelial Fatty Acid Uptake |
| title_fullStr |
EPAS1 Attenuates Atherosclerosis Initiation at Disturbed Flow Sites Through Endothelial Fatty Acid Uptake |
| title_full_unstemmed |
EPAS1 Attenuates Atherosclerosis Initiation at Disturbed Flow Sites Through Endothelial Fatty Acid Uptake |
| title_sort |
EPAS1 Attenuates Atherosclerosis Initiation at Disturbed Flow Sites Through Endothelial Fatty Acid Uptake |
| dc.creator.none.fl_str_mv |
Pirri, D.|||0000-0002-7051-4176 Tian, S. Tardajos-Ayllon, B. Irving, S.E.|||0000-0003-0772-1946 Donati, F.|||0000-0002-5212-1248 Allen, S.P.|||0000-0003-4418-7375 Mammoto, T. Vilahur, Gemma|||0000-0002-2828-8873 Kabir, L. Bennett, J. Rasool, Y. Pericleous, C.|||0000-0001-8804-0493 Mazzei, G. McAllan, L. Scott, W.R.|||0000-0001-5467-114X Koestler, T. Zingg, U. Birdsey, G.M. Miller, C.L.|||0000-0003-4276-3607 Schenkel, T. Chambers, E.V.|||0000-0003-1252-8059 Dunning, M.J.|||0000-0002-8853-9435 Serbanovic-Canic, J.|||0000-0002-8835-1491 Botrè, F.|||0000-0001-5296-8126 Mammoto, A. Xu, S. Osto, Elena|||0000-0001-8196-5696 Han, Weiping Fragiadaki, M.|||0000-0002-1587-5577 Evans, P.C.|||0000-0001-7975-681X |
| author |
Pirri, D.|||0000-0002-7051-4176 |
| author_facet |
Pirri, D.|||0000-0002-7051-4176 Tian, S. Tardajos-Ayllon, B. Irving, S.E.|||0000-0003-0772-1946 Donati, F.|||0000-0002-5212-1248 Allen, S.P.|||0000-0003-4418-7375 Mammoto, T. Vilahur, Gemma|||0000-0002-2828-8873 Kabir, L. Bennett, J. Rasool, Y. Pericleous, C.|||0000-0001-8804-0493 Mazzei, G. McAllan, L. Scott, W.R.|||0000-0001-5467-114X Koestler, T. Zingg, U. Birdsey, G.M. Miller, C.L.|||0000-0003-4276-3607 Schenkel, T. Chambers, E.V.|||0000-0003-1252-8059 Dunning, M.J.|||0000-0002-8853-9435 Serbanovic-Canic, J.|||0000-0002-8835-1491 Botrè, F.|||0000-0001-5296-8126 Mammoto, A. Xu, S. Osto, Elena|||0000-0001-8196-5696 Han, Weiping Fragiadaki, M.|||0000-0002-1587-5577 Evans, P.C.|||0000-0001-7975-681X |
| author_role |
author |
| author2 |
Tian, S. Tardajos-Ayllon, B. Irving, S.E.|||0000-0003-0772-1946 Donati, F.|||0000-0002-5212-1248 Allen, S.P.|||0000-0003-4418-7375 Mammoto, T. Vilahur, Gemma|||0000-0002-2828-8873 Kabir, L. Bennett, J. Rasool, Y. Pericleous, C.|||0000-0001-8804-0493 Mazzei, G. McAllan, L. Scott, W.R.|||0000-0001-5467-114X Koestler, T. Zingg, U. Birdsey, G.M. Miller, C.L.|||0000-0003-4276-3607 Schenkel, T. Chambers, E.V.|||0000-0003-1252-8059 Dunning, M.J.|||0000-0002-8853-9435 Serbanovic-Canic, J.|||0000-0002-8835-1491 Botrè, F.|||0000-0001-5296-8126 Mammoto, A. Xu, S. Osto, Elena|||0000-0001-8196-5696 Han, Weiping Fragiadaki, M.|||0000-0002-1587-5577 Evans, P.C.|||0000-0001-7975-681X |
| author2_role |
author author author author author author author author author author author author author author author author author author author author author author author author author author author author author |
| dc.contributor.none.fl_str_mv |
Universitat Autònoma de Barcelona |
| dc.subject.none.fl_str_mv |
Atherosclerosis Diet, high-fat Endothelial cells Obesity Plaque, atherosclerotic |
| topic |
Atherosclerosis Diet, high-fat Endothelial cells Obesity Plaque, atherosclerotic |
| description |
BACKGROUND: Atherosclerotic plaques form unevenly due to disturbed blood flow, causing localized endothelial cell (EC) dysfunction. Obesity exacerbates this process, but the underlying molecular mechanisms are unclear. The transcription factor EPAS1 (HIF2A) has regulatory roles in endothelium, but its involvement in atherosclerosis remains unexplored. This study investigates the potential interplay between EPAS1, obesity, and atherosclerosis. METHODS: Responses to shear stress were analyzed using cultured porcine aortic EC exposed to flow in vitro coupled with metabolic and molecular analyses and by en face immunostaining of murine aortic EC exposed to disturbed flow in vivo. Obesity and dyslipidemia were induced in mice via exposure to a high-fat diet or through Leptin gene deletion. The role of Epas1 in atherosclerosis was evaluated by inducible endothelial Epas1 deletion, followed by hypercholesterolemia induction (adeno-associated virus-PCSK9 [proprotein convertase subtilisin/kexin type 9]; high-fat diet). RESULTS: En face staining revealed EPAS1 enrichment at sites of disturbed blood flow that are prone to atherosclerosis initiation. Obese mice exhibited substantial reduction in endothelial EPAS1 expression. Sulforaphane, a compound with known atheroprotective effects, restored EPAS1 expression and concurrently reduced plasma triglyceride levels in obese mice. Consistently, triglyceride derivatives (free fatty acids) suppressed EPAS1 in cultured EC by upregulating the negative regulator PHD2. Clinical observations revealed that reduced serum EPAS1 correlated with increased endothelial PHD2 and PHD3 in obese individuals. Functionally, endothelial EPAS1 deletion increased lesion formation in hypercholesterolemic mice, indicating an atheroprotective function. Mechanistic insights revealed that EPAS1 protects arteries by maintaining endothelial proliferation by positively regulating the expression of the fatty acid-handling molecules CD36 (cluster of differentiation 36) and LIPG (endothelial type lipase G) to increase fatty acid beta-oxidation. CONCLUSIONS: Endothelial EPAS1 attenuates atherosclerosis at sites of disturbed flow by maintaining EC proliferation via fatty acid uptake and metabolism. This endothelial repair pathway is inhibited in obesity, suggesting a novel triglyceride-PHD2 modulation pathway suppressing EPAS1 expression. These findings have implications for therapeutic strategies addressing vascular dysfunction in obesity. |
| publishDate |
2024 |
| dc.date.none.fl_str_mv |
2 2024-01-01 2024 2024-01-01 |
| dc.type.none.fl_str_mv |
Article http://purl.org/coar/resource_type/c_6501 VoR http://purl.org/coar/version/c_970fb48d4fbd8a85 |
| dc.type.openaire.fl_str_mv |
info:eu-repo/semantics/article |
| format |
article |
| dc.identifier.none.fl_str_mv |
https://ddd.uab.cat/record/309024 https://dx.doi.org/urn:doi:10.1161/CIRCRESAHA.123.324054 |
| url |
https://ddd.uab.cat/record/309024 https://dx.doi.org/urn:doi:10.1161/CIRCRESAHA.123.324054 |
| dc.language.none.fl_str_mv |
Inglés eng |
| language_invalid_str_mv |
Inglés |
| language |
eng |
| dc.rights.none.fl_str_mv |
open access http://purl.org/coar/access_right/c_abf2 https://creativecommons.org/licenses/by/4.0/ |
| dc.rights.openaire.fl_str_mv |
info:eu-repo/semantics/openAccess |
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open access http://purl.org/coar/access_right/c_abf2 https://creativecommons.org/licenses/by/4.0/ |
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openAccess |
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application/pdf |
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reponame:Dipòsit Digital de Documents de la UAB instname:Universitat Autònoma de Barcelona |
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Universitat Autònoma de Barcelona |
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Dipòsit Digital de Documents de la UAB |
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Dipòsit Digital de Documents de la UAB |
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1869412723748503552 |
| spelling |
EPAS1 Attenuates Atherosclerosis Initiation at Disturbed Flow Sites Through Endothelial Fatty Acid UptakePirri, D.|||0000-0002-7051-4176Tian, S.Tardajos-Ayllon, B.Irving, S.E.|||0000-0003-0772-1946Donati, F.|||0000-0002-5212-1248Allen, S.P.|||0000-0003-4418-7375Mammoto, T.Vilahur, Gemma|||0000-0002-2828-8873Kabir, L.Bennett, J.Rasool, Y.Pericleous, C.|||0000-0001-8804-0493Mazzei, G.McAllan, L.Scott, W.R.|||0000-0001-5467-114XKoestler, T.Zingg, U.Birdsey, G.M.Miller, C.L.|||0000-0003-4276-3607Schenkel, T.Chambers, E.V.|||0000-0003-1252-8059Dunning, M.J.|||0000-0002-8853-9435Serbanovic-Canic, J.|||0000-0002-8835-1491Botrè, F.|||0000-0001-5296-8126Mammoto, A.Xu, S.Osto, Elena|||0000-0001-8196-5696Han, WeipingFragiadaki, M.|||0000-0002-1587-5577Evans, P.C.|||0000-0001-7975-681XAtherosclerosisDiet, high-fatEndothelial cellsObesityPlaque, atheroscleroticBACKGROUND: Atherosclerotic plaques form unevenly due to disturbed blood flow, causing localized endothelial cell (EC) dysfunction. Obesity exacerbates this process, but the underlying molecular mechanisms are unclear. The transcription factor EPAS1 (HIF2A) has regulatory roles in endothelium, but its involvement in atherosclerosis remains unexplored. This study investigates the potential interplay between EPAS1, obesity, and atherosclerosis. METHODS: Responses to shear stress were analyzed using cultured porcine aortic EC exposed to flow in vitro coupled with metabolic and molecular analyses and by en face immunostaining of murine aortic EC exposed to disturbed flow in vivo. Obesity and dyslipidemia were induced in mice via exposure to a high-fat diet or through Leptin gene deletion. The role of Epas1 in atherosclerosis was evaluated by inducible endothelial Epas1 deletion, followed by hypercholesterolemia induction (adeno-associated virus-PCSK9 [proprotein convertase subtilisin/kexin type 9]; high-fat diet). RESULTS: En face staining revealed EPAS1 enrichment at sites of disturbed blood flow that are prone to atherosclerosis initiation. Obese mice exhibited substantial reduction in endothelial EPAS1 expression. Sulforaphane, a compound with known atheroprotective effects, restored EPAS1 expression and concurrently reduced plasma triglyceride levels in obese mice. Consistently, triglyceride derivatives (free fatty acids) suppressed EPAS1 in cultured EC by upregulating the negative regulator PHD2. Clinical observations revealed that reduced serum EPAS1 correlated with increased endothelial PHD2 and PHD3 in obese individuals. Functionally, endothelial EPAS1 deletion increased lesion formation in hypercholesterolemic mice, indicating an atheroprotective function. Mechanistic insights revealed that EPAS1 protects arteries by maintaining endothelial proliferation by positively regulating the expression of the fatty acid-handling molecules CD36 (cluster of differentiation 36) and LIPG (endothelial type lipase G) to increase fatty acid beta-oxidation. CONCLUSIONS: Endothelial EPAS1 attenuates atherosclerosis at sites of disturbed flow by maintaining EC proliferation via fatty acid uptake and metabolism. This endothelial repair pathway is inhibited in obesity, suggesting a novel triglyceride-PHD2 modulation pathway suppressing EPAS1 expression. These findings have implications for therapeutic strategies addressing vascular dysfunction in obesity.Universitat Autònoma de Barcelona 22024-01-0120242024-01-01Articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttps://ddd.uab.cat/record/309024https://dx.doi.org/urn:doi:10.1161/CIRCRESAHA.123.324054reponame:Dipòsit Digital de Documents de la UABinstname:Universitat Autònoma de BarcelonaInglésengopen accesshttp://purl.org/coar/access_right/c_abf2Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.https://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:ddd.uab.cat:3090242026-06-06T12:50:31Z |
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15,811543 |