Lovastatin reduces apoptosis and downregulates the CD40 expression induced by TNF-alpha in cerebral vascular endothelial cells.
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.
Department of Pharmacology, Xi'an Jiaotong University School of Medicine, Xi'an, Shaanxi, P.R. China. linrong@mail.xjtu.edu.cn
Rong
R
Lin
Juntian
J
Liu
Ning
N
Peng
Weijie
W
Gan
Weirong
W
Wang
Chunjie
C
Han
Cunjing
C
Ding
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western / Q000379:methods; D019013:CD40 Antigens / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000033:anatomy & histology; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects*; D004347:Drug Interactions; D042783:Endothelial Cells / Q000187:drug effects*; D004730:Endothelium, Vascular / Q000166:cytology; D008148:Lovastatin / Q000494:pharmacology*; D008954:Models, Biological; D051381:Rats; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D019013:CD40 Antigens; D014409:Tumor Necrosis Factor-alpha; D008148:Lovastatin