EPAS1 Attenuates Atherosclerosis Initiation at Disturbed Flow Sites Through Endothelial Fatty Acid Uptake.

Tools

PIRRI, Daniela, TIAN, Siyu, TARDAJOS-AYLLON, Blanca, IRVING, Sophie E, DONATI, Francesco, ALLEN, Scott P, MAMMOTO, Tadanori, VILAHUR, Gemma, KABIR, Lida, BENNETT, Jane, RASOOL, Yasmin, PERICLEOUS, Charis, MAZZEI, Guianfranco, MCALLAN, Liam, SCOTT, William R, KOESTLER, Thomas, ZINGG, Urs, BIRDSEY, Graeme M, MILLER, Clint L, SCHENKEL, Torsten, CHAMBERS, Emily V, DUNNING, Mark J, SERBANOVIC-CANIC, Jovana, BOTRÈ, Francesco, MAMMOTO, Akiko, XU, Suowen, OSTO, Elena, HAN, Weiping, FRAGIADAKI, Maria and EVANS, Paul C (2024). EPAS1 Attenuates Atherosclerosis Initiation at Disturbed Flow Sites Through Endothelial Fatty Acid Uptake. Circulation research, 135 (8), 822-837. [Article]

Documents
34380:715803
[thumbnail of Schenkel-EPAS1AttenuatesAtherosclerosisInitiation(VoR).pdf]
Preview
PDF
Schenkel-EPAS1AttenuatesAtherosclerosisInitiation(VoR).pdf - Published Version
Available under License Creative Commons Attribution.

Download (10MB) | Preview
Abstract

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.
More Information
Official URL:
http://dx.doi.org/10.1161/circresaha.123.324054
Open Access URL:
https://www.ahajournals.org/doi/epdf/10.1161/CIRCR...
Open Access Version:
Published version
Uncontrolled Keywords:
Endothelium, Vascular; Cells, Cultured; Endothelial Cells; Animals; Mice, Inbred C57BL; Swine; Mice; Obesity; Fatty Acids; Male; Atherosclerosis; Basic Helix-Loop-Helix Transcription Factors; Diet, High-Fat; atherosclerosis; diet, high-fat; endothelial cells; obesity; plaque, atherosclerotic; Animals; Basic Helix-Loop-Helix Transcription Factors; Atherosclerosis; Mice; Endothelial Cells; Obesity; Cells, Cultured; Fatty Acids; Mice, Inbred C57BL; Swine; Male; Diet, High-Fat; Endothelium, Vascular; 1102 Cardiorespiratory Medicine and Haematology; 1103 Clinical Sciences; Cardiovascular System & Hematology; 3201 Cardiovascular medicine and haematology; 3202 Clinical sciences
Page Range:
822-837
Event Location:
United States

Identifiers

Identification Number:
10.1161/circresaha.123.324054
ORCID for Daniela Pirri: ORCID iD orcid.org/0000-0002-7051-4176
ORCID for Blanca Tardajos-Ayllon: ORCID iD orcid.org/0000-0001-6466-8366
ORCID for Sophie E Irving: ORCID iD orcid.org/0000-0003-0772-1946
ORCID for Francesco Donati: ORCID iD orcid.org/0000-0002-5212-1248
ORCID for Scott P Allen: ORCID iD orcid.org/0000-0003-4418-7375
ORCID for Gemma Vilahur: ORCID iD orcid.org/0000-0002-2828-8873
ORCID for Charis Pericleous: ORCID iD orcid.org/0000-0001-8804-0493
ORCID for William R Scott: ORCID iD orcid.org/0000-0001-5467-114X
ORCID for Graeme M Birdsey: ORCID iD orcid.org/0000-0002-0981-8672
ORCID for Clint L Miller: ORCID iD orcid.org/0000-0003-4276-3607
ORCID for Torsten Schenkel: ORCID iD orcid.org/0000-0001-5560-1872
ORCID for Emily V Chambers: ORCID iD orcid.org/0000-0003-1252-8059
ORCID for Mark J Dunning: ORCID iD orcid.org/0000-0002-8853-9435
ORCID for Jovana Serbanovic-Canic: ORCID iD orcid.org/0000-0002-8835-1491
ORCID for Francesco Botrè: ORCID iD orcid.org/0000-0001-5296-8126
ORCID for Elena Osto: ORCID iD orcid.org/0000-0001-8196-5696
ORCID for Maria Fragiadaki: ORCID iD orcid.org/0000-0002-1587-5577
ORCID for Paul C Evans: ORCID iD orcid.org/0000-0001-7975-681X

Library

Item Type:
Article
SWORD Depositor:
Symplectic Elements
Depositing User:
Symplectic Elements
Date Deposited:
24 Oct 2024 14:34
Last Modified:
18 Dec 2024 17:03
Date of first compliant deposit:
24 October 2024
Date of first compliant Open Access:
24 October 2024
Version of first compliant deposit:
Version of Record
URI:
https://shura.shu.ac.uk/id/eprint/34380
Statistics

Downloads

Downloads per month over past year

View more statistics

Metrics

Altmetric Badge

Dimensions Badge

Share
Add to AnyAdd to TwitterAdd to FacebookAdd to LinkedinAdd to PinterestAdd to Email

Actions (login required)

View Item View Item

SHURA supports OAI 2.0 with a base URL of https://shura.shu.ac.uk/cgi/oai2