Norda Stephen, Papadantonaki Rosa
Department of Cardiovascular Medicine, University Hospital Münster, Germany.
Emergency Department, West Middlesex University Hospital, Chelsea and Westminster NHS Trust, London, United Kingdom.
Vasa. 2023 Jan;52(1):6-21. doi: 10.1024/0301-1526/a001044. Epub 2022 Dec 9.
The cell's response to hypoxia depends on stabilization of the hypoxia-inducible factor 1 complex and transactivation of nuclear factor kappa-B (NF-κB). HIF target gene transcription in cells resident to atherosclerotic lesions adjoins a complex interplay of cytokines and mediators of inflammation affecting cholesterol uptake, migration, and inflammation. Maladaptive activation of the HIF-pathway and transactivation of nuclear factor kappa-B causes monocytes to invade early atherosclerotic lesions, maintaining inflammation and aggravating a low-oxygen environment. Meanwhile HIF-dependent upregulation of the ATP-binding cassette transporter ABCA1 causes attenuation of cholesterol efflux and ultimately macrophages becoming foam cells. Hypoxia facilitates neovascularization by upregulation of vascular endothelial growth factor (VEGF) secreted by endothelial cells and vascular smooth muscle cells lining the arterial wall destabilizing the plaque. HIF-knockout animal models and inhibitor studies were able to show beneficial effects on atherogenesis by counteracting the HIF-pathway in the cell wall. In this review the authors elaborate on the up-to-date literature on regulation of cells of the arterial wall through activation of HIF-1α and its effect on atherosclerotic plaque formation.
细胞对缺氧的反应取决于缺氧诱导因子1复合物的稳定以及核因子κB（NF-κB）的反式激活。动脉粥样硬化病变部位细胞中的缺氧诱导因子（HIF）靶基因转录伴随着细胞因子和炎症介质的复杂相互作用，这些因子和介质会影响胆固醇摄取、迁移和炎症反应。HIF通路的适应性激活和核因子κB的反式激活会导致单核细胞侵入早期动脉粥样硬化病变，维持炎症反应并加重低氧环境。同时，ATP结合盒转运体ABCA1的HIF依赖性上调会导致胆固醇流出减弱，最终使巨噬细胞变成泡沫细胞。缺氧通过上调动脉壁内衬的内皮细胞和血管平滑肌细胞分泌的血管内皮生长因子（VEGF）促进新血管形成，从而使斑块不稳定。HIF基因敲除动物模型和抑制剂研究表明，通过对抗细胞壁中的HIF通路，对动脉粥样硬化的发生具有有益作用。在这篇综述中，作者详细阐述了关于通过激活HIF-1α调节动脉壁细胞及其对动脉粥样硬化斑块形成影响的最新文献。
