Cepharanthine inhibits in vitro VSMC proliferation and migration and vascular inflammatory responses mediated by RAW264.7

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Journal Article
Toxicology in Vitro, 2016, 34 pp. 16 - 25
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© 2015 Elsevier B.V. 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.
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