Centre for Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, EC1M 6BQ, UK.
Centre for Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, EC1M 6BQ, UK.
Vascul Pharmacol. 2019 Jan;112:54-71. doi: 10.1016/j.vph.2018.08.002. Epub 2018 Aug 14.
During atherosclerosis, the gradual accumulation of lipids into the subendothelial space of damaged arteries results in several lipid modification processes followed by macrophage uptake in the arterial wall. The way in which these modified lipoproteins are dealt with determines the likelihood of cholesterol accumulation within the monocyte-derived macrophage and thus its transformation into the foam cell that makes up the characteristic fatty streak observed in the early stages of atherosclerosis. The unique expression of chemokine receptors and cellular adhesion molecules expressed on the cell surface of monocytes points to a particular extravasation route that they can take to gain entry into atherosclerotic site, in order to undergo differentiation into the phagocytic macrophage. Indeed several GWAS and animal studies have identified key genes and proteins required for monocyte recruitment as well cholesterol handling involving lipid uptake, cholesterol esterification and cholesterol efflux. A re-examination of the previously accepted paradigm of macrophage foam cell origin has been called into question by recent studies demonstrating shared expression of scavenger receptors, cholesterol transporters and pro-inflammatory cytokine release by alternative cell types present in the neointima, namely; endothelial cells, vascular smooth muscle cells and stem/progenitor cells. Thus, therapeutic targets aimed at a more heterogeneous foam cell population with shared functions, such as enhanced protease activity, and signalling pathways, mediated by non-coding RNA molecules, may provide greater therapeutic outcome in patients. Finally, studies targeting each aspect of foam cell formation and death using both genetic knock down and pharmacological inhibition have provided researchers with a clearer understanding of the cellular processes at play, as well as helped researchers to identify key molecular targets, which may hold significant therapeutic potential in the future.
在动脉粥样硬化中，脂质逐渐积累到受损动脉的内膜下空间，导致几种脂质修饰过程，随后巨噬细胞摄取到动脉壁中。这些修饰的脂蛋白的处理方式决定了胆固醇在单核细胞衍生的巨噬细胞中积累的可能性，从而决定了其转化为泡沫细胞的可能性，泡沫细胞构成了动脉粥样硬化早期观察到的特征性脂肪条纹。单核细胞表面表达的趋化因子受体和细胞黏附分子的独特表达，表明它们可以通过特定的血管外渗途径进入动脉粥样硬化部位，从而分化为吞噬性巨噬细胞。事实上，几项全基因组关联研究和动物研究已经确定了单核细胞募集以及涉及脂质摄取、胆固醇酯化和胆固醇流出所需的关键基因和蛋白质。最近的研究表明，在内膜中存在的替代细胞类型（即内皮细胞、血管平滑肌细胞和干细胞/祖细胞）中，也存在清道夫受体、胆固醇转运蛋白和促炎细胞因子释放的共同表达，这对先前接受的巨噬细胞泡沫细胞起源的范例提出了质疑。因此，针对具有共同功能（如增强蛋白酶活性和由非编码 RNA 分子介导的信号通路）的更异质泡沫细胞群体的治疗靶点，可能会为患者提供更好的治疗效果。最后，使用基因敲除和药理学抑制靶向泡沫细胞形成和死亡的各个方面的研究，为研究人员提供了对细胞过程的更清晰理解，并帮助研究人员确定了关键的分子靶点，这些靶点在未来可能具有重要的治疗潜力。
