Reconstituted High-Density Lipoproteins Rescue Diabetes-Impaired Endothelial Cell Metabolic Reprograming and Angiogenic Responses to Hypoxia.

IF 7.4 1区医学 Q1 HEMATOLOGY

Arteriosclerosis, Thrombosis, and Vascular Biology Pub Date : 2025-03-20 DOI:10.1161/ATVBAHA.124.320110

Khalia R Primer, Joanne T M Tan, Lauren Sandeman, Victoria A Nankivell, Liam G Stretton, Emma L Solly, Peter J Psaltis, Christina A Bursill

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引用次数: 0

Abstract

Background: Impaired angiogenic responses to ischemia underlie diabetic vascular complications. Reconstituted high-density lipoproteins (rHDLs) have proangiogenic effects in diabetes. The PDK4 (pyruvate dehydrogenase kinase 4)/PDC (pyruvate dehydrogenase complex) axis is an oxygen-conserving mechanism that preserves endothelial cell function in hypoxia. We aimed to determine the role of the PDK4/PDC axis in angiogenesis, the effect of diabetes on its regulation in response to ischemia, and the proangiogenic properties of rHDL.

Methods: Expression of PDK4 and phosphorylated PDC (pPDC) were measured in PBS- or rHDL-treated wounds of nondiabetic and streptozotocin-induced diabetic mice and PBS- or rHDL-treated endothelial cells exposed to glucose and hypoxia. The importance of PDK4 in the action of rHDL was determined by siRNA knockdown in vitro and PDK4 inhibitor in vivo. Chromatin immunoprecipitation assay was performed to identify the mechanism for PDK4 induction by rHDL.

Results: PDK4 and pPDC were elevated early (24 hours) post-induction of wound ischemia in nondiabetic wounds, which did not occur in diabetic mice. Topical rHDL rescued this impairment, enhancing PDK4 (68%; P=0.0041) and pPDC (165%; P=0.029) in diabetic wounds. Wound neovascularization (62%; P<0.05) and closure (154%; P<0.001) were increased in diabetic rHDL-treated wounds. In vitro, PDK4 and pPDC levels were increased with hypoxia (65%, P=0.043 and 64%, P=0.026, respectively). High glucose did not elicit a further stepwise induction in PDK4/pPDC, with aberrant increases in mitochondrial respiration (19%; P=0.026), and impaired angiogenic functions. Importantly, rHDL increased PDK4 and pPDC 2-fold, returning mitochondrial respiration and angiogenic functions to normal glucose levels. PDK4 inhibition ameliorated the proangiogenic effects of rHDL. rHDL increased FOXO1 (forkhead box O1) binding to the PDK4 promoter and suppressed FOXO1 phosphorylation, presenting FOXO1 as a mechanism for rHDL-mediated induction of PDK4.

Conclusions: The PDK4/PDC axis response to ischemia is impaired in diabetes and is important for the proangiogenic effects of rHDL.

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重建高密度脂蛋白拯救糖尿病受损内皮细胞代谢重编程和缺氧血管生成反应。

背景：缺血时血管生成反应受损是糖尿病血管并发症的基础。重组高密度脂蛋白（rHDLs）在糖尿病中具有促进血管生成的作用。PDK4（丙酮酸脱氢酶激酶4）/PDC（丙酮酸脱氢酶复合体）轴是一种在缺氧条件下保持内皮细胞功能的保氧机制。我们的目的是确定PDK4/PDC轴在血管生成中的作用，糖尿病对其在缺血反应中的调节作用，以及rHDL的促血管生成特性。方法：测定PBS或rhdl处理的非糖尿病和链脲佐菌素诱导的糖尿病小鼠伤口和PBS或rhdl处理的葡萄糖和缺氧的内皮细胞中PDK4和磷酸化PDC （pPDC）的表达。PDK4在rHDL作用中的重要性通过体外siRNA敲除和体内PDK4抑制剂来确定。采用染色质免疫沉淀法鉴定rHDL诱导PDK4的机制。结果：非糖尿病性创面缺血诱导后早期（24小时）PDK4和pPDC升高，而糖尿病小鼠无此现象。局部rHDL可挽救这种损伤，增强PDK4 (68%；P=0.0041)和pPDC (165%；P=0.029)。伤口新生血管（62%）；PPP=0.043, 64%， P=0.026)。高葡萄糖并没有引起PDK4/pPDC进一步的逐步诱导，线粒体呼吸异常增加(19%；P=0.026)，血管生成功能受损。重要的是，rHDL使PDK4和pPDC增加了2倍，使线粒体呼吸和血管生成功能恢复到正常的血糖水平。抑制PDK4可改善rHDL的促血管生成作用。rHDL增加了FOXO1与PDK4启动子的结合，抑制了FOXO1的磷酸化，表明FOXO1是rHDL介导的PDK4诱导的机制之一。结论：糖尿病患者PDK4/PDC轴对缺血的反应受损，对rHDL的促血管生成作用起重要作用。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Arteriosclerosis, Thrombosis, and Vascular Biology 医学-外周血管病

CiteScore

15.60

自引率

2.30%

发文量

337

审稿时长

2-4 weeks

期刊介绍： The journal "Arteriosclerosis, Thrombosis, and Vascular Biology" (ATVB) is a scientific publication that focuses on the fields of vascular biology, atherosclerosis, and thrombosis. It is a peer-reviewed journal that publishes original research articles, reviews, and other scholarly content related to these areas. The journal is published by the American Heart Association (AHA) and the American Stroke Association (ASA). The journal was published bi-monthly until January 1992, after which it transitioned to a monthly publication schedule. The journal is aimed at a professional audience, including academic cardiologists, vascular biologists, physiologists, pharmacologists and hematologists.