EPAS1 Attenuates Atherosclerosis Initiation at Disturbed Flow Sites Through Endothelial Fatty Acid Uptake
Por:
Pirri, D, Tian, SY, Tardajos-Ayllon, B, Irving, SE, Donati, F, Allen, SP, Mammoto, T, Vilahur, G, Kabir, L, Bennett, J, Rasool, Y, Pericleous, C, Mazzei, G, McAllan, L, Scott, WR, Koestler, T, Zingg, U, Birdsey, GM, Miller, CL, Schenkel, T, Chambers, EV, Dunning, MJ, Serbanovic-Canic, J, Botrè, F, Mammoto, A, Xu, SW, Osto, E, Han, WP, Fragiadaki, M, Evans, PC
Publicada:
27 sep 2024
Resumen:
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.
Filiaciones:
Pirri, D:
Univ Sheffield, INSIGNEO Inst, Sch Med & Populat Hlth, Sheffield, England
Univ Sheffield, Bateson Ctr, Sheffield, England
Imperial Coll London, Natl Heart & Lung Inst, London, England
Tian, SY:
Univ Sheffield, INSIGNEO Inst, Sch Med & Populat Hlth, Sheffield, England
Univ Sheffield, Bateson Ctr, Sheffield, England
Queen Mary Univ London, William Harvey Res Inst, Ctr Biochem Pharmacol, Barts & London Sch Med & Dent, London, England
Tardajos-Ayllon, B:
Queen Mary Univ London, William Harvey Res Inst, Ctr Biochem Pharmacol, Barts & London Sch Med & Dent, London, England
Irving, SE:
Univ Sheffield, INSIGNEO Inst, Sch Med & Populat Hlth, Sheffield, England
Univ Sheffield, Bateson Ctr, Sheffield, England
Donati, F:
Federaz Med Sport Italiana, Lab Antidoping, Rome, Italy
Allen, SP:
Univ Sheffield, Sheffield Inst Translat Neurosci, Sch Med & Populat Hlth, Sheffield, England
Mammoto, T:
Med Coll Wisconsin, Dept Pediat, Milwaukee, WI USA
Med Coll Wisconsin, Dept Pharmacol & Toxicol, Milwaukee, WI USA
Vilahur, G:
Inst Recerca Hosp Santa Creu & St Pau, IIB St Pau, Barcelona, Spain
Inst Salud Carlos III, CIBERCV Ctr Invest Red Enfermedades Cardiovasc, Barcelona, Spain
Kabir, L:
Med Res Council MRC, Lab Med Sci, London, England
Bennett, J:
Med Res Council MRC, Lab Med Sci, London, England
Rasool, Y:
Med Res Council MRC, Lab Med Sci, London, England
Imperial Coll London, Inst Clin Sci, Fac Med, London, England
Pericleous, C:
Limmattal Hosp, Bariatr Ctr, Dept Surg, Schlieren, Switzerland
Mazzei, G:
Med Res Council MRC, Lab Med Sci, London, England
Imperial Coll London, Inst Clin Sci, Fac Med, London, England
McAllan, L:
Med Res Council MRC, Lab Med Sci, London, England
Imperial Coll London, Inst Clin Sci, Fac Med, London, England
Scott, WR:
Med Res Council MRC, Lab Med Sci, London, England
Imperial Coll London, Inst Clin Sci, Fac Med, London, England
Koestler, T:
Limmattal Hosp, Bariatr Ctr, Dept Surg, Schlieren, Switzerland
Zingg, U:
Limmattal Hosp, Bariatr Ctr, Dept Surg, Schlieren, Switzerland
Birdsey, GM:
Imperial Coll London, Natl Heart & Lung Inst, London, England
Miller, CL:
Univ Virginia, Ctr Publ Hlth Genom, Dept Publ Hlth Sci, Charlottesville, VA USA
Schenkel, T:
Sheffield Hallam Univ, Dept Engn & Math, Sheffield, England
Chambers, EV:
Univ Sheffield, Sch Med & Populat Hlth, Sheffield Bioinformat Core, Sheffield, England
Dunning, MJ:
Univ Sheffield, Sch Med & Populat Hlth, Sheffield Bioinformat Core, Sheffield, England
Serbanovic-Canic, J:
Univ Sheffield, INSIGNEO Inst, Sch Med & Populat Hlth, Sheffield, England
Univ Sheffield, Bateson Ctr, Sheffield, England
Botrè, F:
Federaz Med Sport Italiana, Lab Antidoping, Rome, Italy
Mammoto, A:
Med Coll Wisconsin, Dept Pediat, Milwaukee, WI USA
Med Coll Wisconsin, Dept Cell Biol Neurobiol & Anat, Milwaukee, WI USA
Xu, SW:
Chinese Acad Sci Hefei, Univ Sci & Technol China USTC, Inst Endocrine & Metab Dis, ,Affiliated Hosp 1,Div Life Sci & Med,Clin Res Hos, Hefei, Peoples R China
Osto, E:
Univ Hosp, Inst Clin Chem, Zurich, Switzerland
Univ Zurich, Zurich, Switzerland
Med Univ Graz, Otto Loewi Res Ctr, Div Physiol & Pathophysiol, Graz, Austria
Han, WP:
ASTAR, Inst Mol & Cell Biol, Singapore, Singapore
Fragiadaki, M:
Queen Mary Univ London, William Harvey Res Inst, Ctr Translat Med & Therapeut, Barts & London Sch Med & Dent, London, England
Evans, PC:
Queen Mary Univ London, William Harvey Res Inst, Ctr Biochem Pharmacol, Barts & London Sch Med & Dent, London, England
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