Lin Rong, Liu Juntian, Peng Ning, Gan Weijie, Wang Weirong, Han Chunjie, Ding Cunjing
Department of Pharmacology, Xi'an Jiaotong University School of Medicine, Xi'an, Shaanxi, P.R. China.
Curr Neurovasc Res. 2006 Feb;3(1):41-7. doi: 10.2174/156720206775541796.
Inflammation may be one of the independent risk factors contributing to many neurological diseases. Moreover, there is an emerging body of data indicating that statins may have neuroprotective action. Recent studies suggest that CD40-CD40 ligand (CD40L) system is proven to be an important mediator of several auto-immune and chronic inflammation diseases. To address whether lovastatin produces neuroprotection as a potential novel anti-inflammatory pathway through the inhibition of CD40 expression, we examined the possible effects of lovastatin on expression of CD40, apoptosis, level of nitric oxide (NO) and nitric oxide synthase (NOS) activity induced by tumor necrosis factor alpha (TNF-alpha) in the cerebral vascular endothelial cells (CVECs) involved in cerebrovascular diseases. Preincubation with lovastatin (10(-7), 10(-6) and 10(-5) mol/l) for 24 hours (h) protected CVECs from TNF-alpha-induced decrease of cellular viability. Further, lovastatin inhibited the TNF-alpha-induced increases of NO level, NOS activity, apoptotic cells and CD40 expression in a dose-dependent manner, and anti-CD40 antibody also inhibited the cellular apoptosis induced by TNF-alpha. In conclusion, our data provide evidence to support a direct pro-inflammatory effect of CD40-CD40L signaling pathway in CVECs, and lovastatin possesses an anti-inflammatory effect independent of its lipid-lowering action involved in the cerebrovascular diseases.
炎症可能是导致多种神经疾病的独立危险因素之一。此外，越来越多的数据表明他汀类药物可能具有神经保护作用。最近的研究表明，CD40-CD40配体（CD40L）系统被证明是几种自身免疫性和慢性炎症性疾病的重要介质。为了探讨洛伐他汀是否通过抑制CD40表达作为一种潜在的新型抗炎途径产生神经保护作用，我们研究了洛伐他汀对参与脑血管疾病的脑血管内皮细胞（CVECs）中CD40表达、细胞凋亡、一氧化氮（NO）水平和一氧化氮合酶（NOS）活性的影响，这些影响是由肿瘤坏死因子α（TNF-α）诱导的。用洛伐他汀（10^(-7)、10^(-6)和10^(-5) mol/l）预孵育24小时可保护CVECs免受TNF-α诱导的细胞活力下降。此外，洛伐他汀以剂量依赖的方式抑制TNF-α诱导的NO水平、NOS活性、凋亡细胞和CD40表达的增加，抗CD40抗体也抑制TNF-α诱导的细胞凋亡。总之，我们的数据提供了证据支持CD40-CD40L信号通路在CVECs中具有直接促炎作用，并且洛伐他汀具有抗炎作用，与其在脑血管疾病中参与的降脂作用无关。
