Immunobiology Research Group, Heart Research Institute, 7 Eliza Street, Newtown, NSW 2042, Australia.
Discipline of Medicine, The University of Sydney School of Medicine, Camperdown, NSW 2006, Australia.
Int J Mol Sci. 2018 Jun 28;19(7):1903. doi: 10.3390/ijms19071903.
Angiogenesis, the process of forming new blood vessels, is crucial in the physiological response to ischemia, though it can be detrimental as part of inflammation and tumorigenesis. We have previously shown that high-density lipoproteins (HDL) modulate angiogenesis in a context-specific manner via distinct classical signalling pathways, enhancing hypoxia-induced angiogenesis while suppressing inflammatory-driven angiogenesis. Whether additional novel targets exist to account for these effects are unknown. A microarray approach identified two novel genes, cyclic-adenosine-monophosphate-response-element-binding protein 3 regulatory factor () and tripartite motif-containing protein 2 () that were upregulated by reconstituted HDL (rHDL). We measured and expression in human coronary artery endothelial cells following incubation with rHDL and exposure to either hypoxia or an inflammatory stimulus. We found that and mRNA were significantly upregulated by rHDL, particularly in response to its phospholipid component 1-palmitoyl-2-linoleoyl-phosphatidylcholine, however, protein expression was not significantly altered. Knockdown of impaired endothelial cell tubulogenesis in vitro in both hypoxia and inflammation, implying a necessary role in angiogenesis. Furthermore, knockdown attenuated rHDL-induced tubule formation in hypoxia, suggesting that it is important in mediating the pro-angiogenic action of rHDL. Our study has implications for understanding the regulation of angiogenesis in both of these pathophysiological contexts by HDL.
血管生成，即新血管形成的过程，在缺血的生理反应中至关重要，但作为炎症和肿瘤发生的一部分，它可能是有害的。我们之前已经表明，高密度脂蛋白（HDL）通过不同的经典信号通路以特定于上下文的方式调节血管生成，增强缺氧诱导的血管生成，同时抑制炎症驱动的血管生成。是否存在其他新的靶点来解释这些作用尚不清楚。微阵列方法鉴定出两种新基因，环腺苷酸反应元件结合蛋白 3 调节因子 () 和三部分基序蛋白 2 ()，它们被重组高密度脂蛋白（rHDL）上调。我们在人冠状动脉内皮细胞孵育 rHDL 并暴露于缺氧或炎症刺激后测量 和 的表达。我们发现 rHDL 显著上调 和 的 mRNA，特别是对其磷脂成分 1-棕榈酰-2-亚油酰-磷酸胆碱的反应，但蛋白质表达没有明显改变。 敲低可损害缺氧和炎症条件下体外内皮细胞小管形成，暗示其在血管生成中具有必要作用。此外，rHDL 诱导的缺氧小管形成被 敲低所抑制，表明其在介导 rHDL 的促血管生成作用中很重要。我们的研究对理解 HDL 在这两种病理生理环境中的血管生成调节具有重要意义。
