EPAS1 Attenuates Atherosclerosis Initiation at Disturbed Flow Sites Through Endothelial Fatty Acid Uptake
Pirri, D. (Imperial College London)
Tian, S. (Queen Mary University of London)
Tardajos-Ayllon, B. (Queen Mary University of London)
Irving, S.E. (University of Sheffield)
Donati, F. (Federazione Medico Sportiva Italiana)
Allen, S.P. (University of Sheffield)
Mammoto, T. (Medical College of Wisconsin)
Vilahur, Gemma (Institut de Recerca Sant Pau)
Kabir, L. (Medical Research Council (MRC) Laboratory of Medical Sciences)
Bennett, J. (Medical Research Council (MRC) Laboratory of Medical Sciences)
Rasool, Y. (Imperial College London)
Pericleous, C. (Limmattal Hospital)
Mazzei, G. (Imperial College London)
McAllan, L. (Imperial College London)
Scott, W.R. (Imperial College London)
Koestler, T. (Limmattal Hospital)
Zingg, U. (Limmattal Hospital)
Birdsey, G.M. (Imperial College London)
Miller, C.L. (University of Virginia)
Schenkel, T. (Sheffield Hallam University)
Chambers, E.V. (University of Sheffield)
Dunning, M.J. (University of Sheffield)
Serbanovic-Canic, J. (University of Sheffield)
Botrè, F. (Federazione Medico Sportiva Italiana)
Mammoto, A. (Medical College of Wisconsin)
Xu, S. (University of Science and Technology of China)
Osto, Elena (Medical University of Graz)
Han, Weiping (Institute of Molecular and Cell Biology. Agency for Science. Technology and Research (A*STAR))
Fragiadaki, M. (Queen Mary University of London)
Evans, P.C. (Queen Mary University of London)
Universitat Autònoma de Barcelona

Data:	2024
Resum:	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.
Drets:	Aquest 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.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Atherosclerosis ; Diet, high-fat ; Endothelial cells ; Obesity ; Plaque, atherosclerotic
Publicat a:	Circulation Research, Vol. 135 Núm. 8 (27 2024) , p. 822-837, ISSN 1524-4571

DOI: 10.1161/CIRCRESAHA.123.324054
PMID: 39234692

16 p, 10.3 MB

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