Paudel Keshav Raj, Karki Rajendra, Kim Dong-Wook
Department of Oriental Medicine Resources, Mokpo National University, Muan-gun, Jeonnam 534-729, Republic of Korea.
Department of Oriental Medicine Resources, Mokpo National University, Muan-gun, Jeonnam 534-729, Republic of Korea.
Toxicol In Vitro. 2016 Aug;34:16-25. doi: 10.1016/j.tiv.2016.03.010. Epub 2016 Mar 25.
Pathogenesis of atherosclerosis involves vascular smooth muscle cell (VSMC) migration and proliferation followed by an inflammation mediated by activated macrophages in the tunica intima of blood vessels. Cepharanthine (CEP) belongs to bisbenzylisoquinoline alkaloids found in the plant Stephania cepharantha, which has been used for various diseases like cancer, alopecia areata, venomous snakebites, and malaria. In this study, we investigated whether CEP suppresses VSMC migration and proliferation and inhibits inflammatory mediator production in macrophage (RAW264.7). Our results showed that CEP possessed significant DPPH scavenging and metal chelating activities. It also markedly inhibited lipid peroxidation. Similarly, CEP suppressed the nitric oxide (NO) production and expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX-2) in RAW264.7 cells. Moreover, the level of prostaglandin E2 was also suppressed and the formation of macrophage derived foam cell was attenuated in RAW264.7 cells. Likewise, NO production in isolated peritoneal macrophage and VSMC migration in response to LPS stimulated RAW264.7 was also halted by CEP treatment. Also, VSMC migration induced by platelet-derived growth factor (PDGF-BB) was inhibited by CEP dose dependently. The anti-migratory effect of CEP on VSMCs was due to its inhibitory effect on metalloproteinase-9 (MMP-9) expression, preventing the degradation of extracellular matrix (ECM) component. Furthermore, CEP suppressed PDGF-BB induced VSMC proliferation by down-regulation of mitogen activated protein kinase (MAPK) signaling molecules. CEP also inhibited the translocation of NF-κB from cytosol to nucleus. Thus, our results suggest that CEP exerts potent anti-atherosclerotic effect through attenuation of inflammation, lipid peroxidation and VSMC migration and proliferation.
动脉粥样硬化的发病机制涉及血管平滑肌细胞（VSMC）迁移和增殖，随后是血管内膜中活化巨噬细胞介导的炎症。千金藤素（CEP）属于在植物头花千金藤中发现的双苄基异喹啉生物碱，该植物已被用于治疗各种疾病，如癌症、斑秃、毒蛇咬伤和疟疾。在本研究中，我们研究了CEP是否能抑制VSMC迁移和增殖，并抑制巨噬细胞（RAW264.7）中炎症介质的产生。我们的结果表明，CEP具有显著的DPPH清除和金属螯合活性。它还能显著抑制脂质过氧化。同样，CEP抑制RAW264.7细胞中一氧化氮（NO）的产生以及诱导型一氧化氮合酶（iNOS）和环氧化酶（COX-2）的表达。此外，RAW264.7细胞中前列腺素E2的水平也受到抑制，巨噬细胞衍生泡沫细胞的形成也有所减弱。同样，CEP处理也能阻止分离的腹膜巨噬细胞中NO的产生以及对LPS刺激的RAW264.7的反应中VSMC迁移。此外，血小板衍生生长因子（PDGF-BB）诱导的VSMC迁移也被CEP剂量依赖性抑制。CEP对VSMCs的抗迁移作用归因于其对金属蛋白酶-9（MMP-9）表达的抑制作用，从而防止细胞外基质（ECM）成分的降解。此外，CEP通过下调丝裂原活化蛋白激酶（MAPK）信号分子来抑制PDGF-BB诱导的VSMC增殖。CEP还抑制NF-κB从细胞质向细胞核的转位。因此，我们的结果表明，CEP通过减轻炎症、脂质过氧化以及VSMC迁移和增殖发挥强大的抗动脉粥样硬化作用。
