兔主动脉平滑肌细胞低密度脂蛋白受体相关蛋白(LRP)的诱导表达调节

在兔主动脉平滑肌细胞 ( SMC)培养基中分别加入正常低密度脂蛋白 ( N- LDL)、氧化低密度脂蛋白 ( ox- LDL)、正常极低密度脂蛋白 ( N- VLDL)、氧化极低密度脂蛋白 ( ox- VLDL)和 β-极低密度脂蛋白 (β- VLDL )培养 2 4 h后 ,用定量 RT- PCR和配体结合实验检测平滑肌细胞 LRP的m RNA和蛋白质水平的表达 .结果表明 :五种脂蛋白均能在转录和翻译水平诱导兔主动脉平滑肌细胞的 LRP表达 ,尤以富含胆固醇的 N- LDL ,ox- LDL和β- VLDL的刺激作用更明显 .用胆固醇单独或与脂蛋白共同温育 SMC后 ,发现胆固醇本身可促进 SMC的 LRP蛋白水平的表达 ,脂蛋白与胆固醇的共同刺激作用更为显著 .结果提示 :上述五种脂蛋白对 SMC上 LRP的表达有上调作用 ,其机制可能主要是通过其中的胆固醇来实现的 .     

Differential effects of low density lipoproteins on insulin-like growth factor-1 (IGF-1) and IGF-1 receptor expression in vascular smooth muscle cells

Low density lipoproteins (LDLs) play an important role in the pathogenesis of atherosclerosis. LDL has been shown to be mitogenic and proapoptotic for vascular smooth muscle cells. However, the mechanisms are poorly understood and may result from an alteration in intracellular mitogenic signaling either directly by LDL or indirectly through an autocrine effect involving growth factor secretion and/or growth factor receptor expression. Insulin-like growth factor-1 (IGF-1) is an autocrine/paracrine factor for vascular smooth muscle cells and has potent anti-apoptotic effects. Thus, we hypothesized that part of the proliferative responses to LDLs may be explained by its modulation of IGF-1 or IGF-1 receptor (IGF-1R) expression. Treatment of rat vascular smooth muscle cells with increasing doses of native LDL dose-dependently increased IGF-1 mRNA by up to 2.6-fold; however, native LDL had no effect on IGF-1R mRNA expression. In contrast, the same doses of oxidized LDL significantly reduced IGF-1 and IGF-1R mRNA by 80 and 61%, respectively, and reduced IGF-1 and IGF-1R protein expression by 63 and 46%. In addition, native and oxidized LDL significantly increased IGF-1-binding protein-2 and IGF-1-binding protein-4 expression as measured by Western ligand blot. Most interestingly, anti-IGF-1 antiserum completely inhibited LDL-induced but not serum-induced increase in (3)H-thymidine incorporation, indicating a requirement for IGF-1 in the LDL-stimulated mitogenic signaling pathway. In summary, these results suggest that native and oxidized LDLs have differential effects on IGF-1 and IGF-1R expression. Because IGF-1 is a potent survival factor for vascular smooth muscle cells, our findings suggest that moderately oxidized LDL may favor proliferation of smooth muscle cells, whereas oxidized LDL may contribute to plaque apoptosis by local depletion of IGF-1 and IGF-1R.