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

IF 16.5 1区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS Circulation research Pub Date : 2024-09-27 Epub Date: 2024-09-05 DOI:10.1161/CIRCRESAHA.123.324054
Daniela Pirri, Siyu Tian, Blanca Tardajos-Ayllon, Sophie E Irving, Francesco Donati, Scott P Allen, Tadanori Mammoto, Gemma Vilahur, Lida Kabir, Jane Bennett, Yasmin Rasool, Charis Pericleous, Guianfranco Mazzei, Liam McAllan, William R Scott, Thomas Koestler, Urs Zingg, Graeme M Birdsey, Clint L Miller, Torsten Schenkel, Emily V Chambers, Mark J Dunning, Jovana Serbanovic-Canic, Francesco Botrè, Akiko Mammoto, Suowen Xu, Elena Osto, Weiping Han, Maria Fragiadaki, Paul C Evans
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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.

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EPAS1 通过内皮脂肪酸的摄取减轻动脉粥样硬化在紊乱血流部位的发生。
背景:动脉粥样硬化斑块因血流紊乱而形成不均,导致局部内皮细胞(EC)功能障碍。肥胖会加剧这一过程,但其潜在的分子机制尚不清楚。转录因子 EPAS1(HIF2A)在内皮中具有调节作用,但其在动脉粥样硬化中的参与作用仍未得到探讨。本研究探讨了 EPAS1、肥胖和动脉粥样硬化之间的潜在相互作用:方法:使用体外暴露于流动的培养猪主动脉 EC,结合代谢和分子分析,并通过对体内暴露于紊乱流动的鼠主动脉 EC 进行正面免疫染色,分析其对剪切应力的反应。通过高脂饮食或Leptin基因缺失诱导小鼠肥胖和血脂异常。通过诱导性内皮 Epas1 基因缺失和高胆固醇血症诱导(腺相关病毒-PCSK9 [proprotein convertase subtilisin/kexin type 9]; 高脂饮食)评估 Epas1 在动脉粥样硬化中的作用:正面染色显示,EPAS1富集在容易引发动脉粥样硬化的血流紊乱部位。肥胖小鼠的内皮 EPAS1 表达量大幅减少。已知具有动脉粥样硬化保护作用的化合物 Sulforaphane 可恢复 EPAS1 的表达,同时降低肥胖小鼠的血浆甘油三酯水平。同样,甘油三酯衍生物(游离脂肪酸)通过上调负调控因子 PHD2 抑制了培养 EC 中的 EPAS1。临床观察显示,血清 EPAS1 的降低与肥胖者内皮 PHD2 和 PHD3 的升高相关。从功能上讲,内皮 EPAS1 基因缺失会增加高胆固醇血症小鼠的病变形成,表明其具有动脉粥样硬化保护功能。机理研究发现,EPAS1通过正向调节脂肪酸处理分子CD36和LIPG的表达以增加脂肪酸β-氧化,从而维持内皮增殖,从而保护动脉:内皮 EPAS1 通过脂肪酸摄取和代谢维持内皮细胞增殖,从而减轻血流紊乱部位的动脉粥样硬化。这一内皮修复途径在肥胖症中受到抑制,表明一种新型甘油三酯-PHD2调节途径抑制了EPAS1的表达。这些发现对解决肥胖症血管功能障碍的治疗策略具有重要意义。
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来源期刊
Circulation research
Circulation research 医学-外周血管病
CiteScore
29.60
自引率
2.00%
发文量
535
审稿时长
3-6 weeks
期刊介绍: Circulation Research is a peer-reviewed journal that serves as a forum for the highest quality research in basic cardiovascular biology. The journal publishes studies that utilize state-of-the-art approaches to investigate mechanisms of human disease, as well as translational and clinical research that provide fundamental insights into the basis of disease and the mechanism of therapies. Circulation Research has a broad audience that includes clinical and academic cardiologists, basic cardiovascular scientists, physiologists, cellular and molecular biologists, and cardiovascular pharmacologists. The journal aims to advance the understanding of cardiovascular biology and disease by disseminating cutting-edge research to these diverse communities. In terms of indexing, Circulation Research is included in several prominent scientific databases, including BIOSIS, CAB Abstracts, Chemical Abstracts, Current Contents, EMBASE, and MEDLINE. This ensures that the journal's articles are easily discoverable and accessible to researchers in the field. Overall, Circulation Research is a reputable publication that attracts high-quality research and provides a platform for the dissemination of important findings in basic cardiovascular biology and its translational and clinical applications.
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