Vijayagopal P, Glancy D L
Department of Medicine, Louisiana State University Medical Center, New Orleans 70112, USA.
Arterioscler Thromb Vasc Biol. 1996 Sep;16(9):1112-21. doi: 10.1161/01.atv.16.9.1112.
Foam cells of atherosclerotic lesions originate from both macrophages and smooth muscle cells (SMCs). We explored the mechanism by which SMCs may become lipid laden. Confluent bovine aortic SMCs were cocultured with P388D, macrophages, and the cocultures were incubated for various times with low-density lipoprotein (LDL), acetyl-LDL, or lipoprotein-proteoglycan (PG) complex isolated from human atherosclerotic lesions. Macrophages were then removed from the SMCs and the cholesteryl ester (CE) content of the SMCs was quantitated. Lipoprotein-PG complex but not LDL or acetyl-LDL produced a 6-fold to 9-fold stimulation of CE synthesis and a 4.4-fold increase in cellular CE mass in cocultured SMCs relative to control SMCs. In similar studies with human aortic SMC-macrophage cocultures, macrophages stimulated lipoprotein-PG complex-mediated CE synthesis 7-fold to 13-fold and CE mass 7.8-fold in cocultured SMCs compared with SMCs cultured alone. CE synthesis that was mediated by lipoprotein-PG complex was dose dependent and increased linearly with time. Incubation of lipoprotein-PG complex with SMC-macrophage cocultures but not with SMCs or macrophages alone resulted in aggregation of the complex and stimulation of cholesterol esterification in SMCs by the conditioned media containing the aggregated complex. Cytochalasin D, an inhibitor of phagocytosis, inhibited CE synthesis mediated by lipoprotein-PG complex by 73%, whereas polyinosinic acid, an inhibitor of the scavenger receptor, had no effect. Upregulation or downregulation of apolipoprotein B,E receptors did not affect the lipoprotein-PG complex-mediated CE synthesis by cocultured SMCs. Lipoprotein-PG complex did not stimulate CE synthesis in SMCs cocultured with aortic endothelial cells or macrophages cocultured with SMCs. These results indicate that macrophages can stimulate CE synthesis and accumulation in cocultured SMCs when incubated with lipoprotein-PG complexes isolated from atherosclerotic lesions. This could be a potential mechanism for myocyte foam cell formation.
动脉粥样硬化病变中的泡沫细胞起源于巨噬细胞和平滑肌细胞（SMC）。我们探究了SMC可能变成脂质负载细胞的机制。将汇合的牛主动脉SMC与P388D、巨噬细胞共培养，并将共培养物与低密度脂蛋白（LDL）、乙酰化LDL或从人类动脉粥样硬化病变中分离出的脂蛋白-蛋白聚糖（PG）复合物孵育不同时间。然后从SMC中去除巨噬细胞，并对SMC的胆固醇酯（CE）含量进行定量。相对于对照SMC，脂蛋白-PG复合物而非LDL或乙酰化LDL使共培养的SMC中CE合成受到6至9倍的刺激，细胞CE质量增加4.4倍。在用人主动脉SMC-巨噬细胞共培养物进行的类似研究中，与单独培养的SMC相比，巨噬细胞刺激共培养的SMC中脂蛋白-PG复合物介导的CE合成增加7至13倍，CE质量增加7.8倍。脂蛋白-PG复合物介导的CE合成呈剂量依赖性，并随时间呈线性增加。脂蛋白-PG复合物与SMC-巨噬细胞共培养物孵育，但不与单独的SMC或巨噬细胞孵育，导致复合物聚集，并通过含有聚集复合物的条件培养基刺激SMC中的胆固醇酯化。吞噬作用抑制剂细胞松弛素D抑制脂蛋白-PG复合物介导的CE合成达73%，而清道夫受体抑制剂多聚肌苷酸则无作用。载脂蛋白B、E受体的上调或下调不影响共培养的SMC中脂蛋白-PG复合物介导的CE合成。脂蛋白-PG复合物不会刺激与主动脉内皮细胞共培养的SMC或与SMC共培养的巨噬细胞中的CE合成。这些结果表明，当与从动脉粥样硬化病变中分离出的脂蛋白-PG复合物孵育时，巨噬细胞可刺激共培养的SMC中CE的合成和积累。这可能是心肌细胞泡沫细胞形成的潜在机制。
