Lo Huey-Ming, Hung Chi-Feng, Tseng Yu-Lun, Chen Bing-Huei, Jian Jr-Shian, Wu Wen-Bin
School of Medicine, Fu-Jen Catholic University, Taipei County, Taiwan.
Biochem Pharmacol. 2007 Jun 30;74(1):54-63. doi: 10.1016/j.bcp.2007.03.017. Epub 2007 Mar 24.
Cardiovascular diseases (CVDs) result from the sub-endothelial accumulation of inflammatory cells and smooth muscle cells (SMCs). Lycopene, a natural compound from tomato, has been suggested to play a role in CVD prevention. However, its action mechanism is still largely unknown. In this study, we examined the effect of lycopene on SMCs. We found that preincubation of PDGF-BB with lycopene resulted in a marked inhibition on PDGF-BB-induced PDGF receptor-beta (PDGFR-beta), PLCgamma, and ERK1/2 phosphorylation in rat A10 SMCs and primary cultured aortic SMCs. In striking contrast, lycopene did not influence EGF-induced ERK1/2 phosphorylation. Surprisingly, further analysis indicates that lycopene could directly bind PDGF-BB and inhibit PDGF-BB-SMC interaction, as determined by dot binding assay and Western blotting. In functional studies, lycopene inhibited PDGF-BB-induced SMC proliferation and migration toward gelatin and collagen at concentrations ranging from 2 to 10 microM. On the contrary, lycopene did not inhibit bFGF- and VEGF-induced endothelial cell migration. Gelatin zymography demonstrated that lycopene's effect on SMC migration was not due to the inhibition of matrix metalloproteinases (MMPs). Taken together, our results provide the first evidence showing that lycopene inhibits PDGF-BB-induced signaling, proliferation and migration in rat A10 and aortic SMCs. One of the action mechanisms is that lycopene is capable of binding PDGF-BB and inhibiting its interaction with SMC, which is quite different from those previously developed PDGFR-beta antagonists. The results presented here may help us to better understand the beneficial effects of lycopene in CVD prevention.
心血管疾病（CVDs）是由炎症细胞和平滑肌细胞（SMCs）在内皮下积累所致。番茄红素是一种来自番茄的天然化合物，已被认为在预防心血管疾病中发挥作用。然而，其作用机制仍 largely 未知。在本研究中，我们检测了番茄红素对 SMCs 的影响。我们发现，番茄红素与血小板源性生长因子 -BB（PDGF-BB）预孵育可显著抑制 PDGF-BB 诱导的大鼠 A10 SMCs 和原代培养的主动脉 SMCs 中血小板源性生长因子受体 -β（PDGFR-β）、磷脂酶 Cγ（PLCγ）和细胞外信号调节激酶 1/2（ERK1/2）的磷酸化。与之形成鲜明对比的是，番茄红素不影响表皮生长因子（EGF）诱导的 ERK1/2 磷酸化。令人惊讶的是，进一步分析表明，通过斑点结合试验和蛋白质印迹法测定，番茄红素可直接结合 PDGF-BB 并抑制 PDGF-BB 与 SMC 的相互作用。在功能研究中，番茄红素在 2 至 10 μM 的浓度范围内抑制 PDGF-BB 诱导的 SMC 增殖以及向明胶和胶原蛋白的迁移。相反，番茄红素不抑制碱性成纤维细胞生长因子（bFGF）和血管内皮生长因子（VEGF）诱导的内皮细胞迁移。明胶酶谱分析表明，番茄红素对 SMC 迁移的影响并非由于对基质金属蛋白酶（MMPs）的抑制。综上所述，我们的结果首次证明番茄红素抑制 PDGF-BB 诱导的大鼠 A10 和主动脉 SMCs 的信号传导、增殖和迁移。其作用机制之一是番茄红素能够结合 PDGF-BB 并抑制其与 SMC 的相互作用，这与先前开发的 PDGFR-β拮抗剂不同。此处呈现的结果可能有助于我们更好地理解番茄红素在预防心血管疾病中的有益作用。
