Molecular and Cellular Physiology Department, Albany Medical College, Albany, NY, 12208, USA.
Sci Rep. 2023 Nov 9;13(1):19588. doi: 10.1038/s41598-023-46467-4.
Arterial macrophage foam cells are filled with cholesterol ester (CE) stored in cytosolic lipid droplets (LDs). Foam cells are central players in progression of atherosclerosis as regulators of lipid metabolism and inflammation, two major driving forces of atherosclerosis development. Thus, foam cells are considered plausible targets for intervention in atherosclerosis. However, a compound that directly regulates the lipid metabolism of LDs in the arterial foam cells has not yet been identified. In this study, we screened compounds that inhibit macrophage foam cell formation using a library of 2697 FDA-approved drugs. From the foam cells generated via loading of human oxidized low-density lipoprotein (oxLDL), we found 21 and 6 compounds that reduced and enhanced accumulations of lipids respectively. Among them, verteporfin most significantly reduced oxLDL-induced foam cell formation whereas it did not display a significant impact on foam cell formation induced by fatty acid. Mechanistically our data demonstrate that verteporfin acts via inhibition of oxLDL association with macrophages, reducing accumulation of CE. Interestingly, while other drugs that reduced foam cell formation did not have impact on pre-existing foam cells, verteporfin treatment significantly reduced their total lipids, CE, and pro-inflammatory gene expression. Together, our study identifies verteporfin as a novel regulator of foam cell lipid metabolism and inflammation and a potential compound for intervention in atherosclerosis.
动脉巨噬细胞泡沫细胞充满了储存在细胞质脂滴 (LDs) 中的胆固醇酯 (CE)。泡沫细胞是动脉粥样硬化进展的核心参与者，作为脂质代谢和炎症的调节剂，这两者是动脉粥样硬化发展的两个主要驱动力。因此，泡沫细胞被认为是动脉粥样硬化干预的合理靶点。然而，尚未发现一种可直接调节动脉泡沫细胞中 LDs 脂质代谢的化合物。在这项研究中，我们使用了 2697 种已获 FDA 批准的药物库，筛选了抑制巨噬细胞泡沫细胞形成的化合物。从负载人氧化低密度脂蛋白 (oxLDL) 的泡沫细胞中，我们发现了 21 种和 6 种分别减少和增加脂质积累的化合物。其中，维替泊芬最显著地减少了 oxLDL 诱导的泡沫细胞形成，而对脂肪酸诱导的泡沫细胞形成没有显著影响。从机制上讲，我们的数据表明维替泊芬通过抑制 oxLDL 与巨噬细胞的结合，减少 CE 的积累。有趣的是，虽然其他减少泡沫细胞形成的药物对已存在的泡沫细胞没有影响，但维替泊芬处理显著降低了它们的总脂质、CE 和促炎基因表达。总之，我们的研究将维替泊芬鉴定为泡沫细胞脂质代谢和炎症的新型调节剂，也是干预动脉粥样硬化的潜在化合物。
