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Inhibition of phosphoinositide 3 kinase‐Akt (protein kinase B)–nuclear factor‐κB pathway by lovastatin limits endothelial–monocyte cell interaction
Author(s) -
Prasad Ratna,
Giri Shailendra,
Nath Narender,
Singh Inderjit,
Singh Avtar K.
Publication year - 2005
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2005.03182.x
Subject(s) - protein kinase b , cell adhesion molecule , microbiology and biotechnology , pi3k/akt/mtor pathway , lovastatin , endothelial stem cell , cell adhesion , biology , cancer research , signal transduction , chemistry , biochemistry , cell , in vitro , cholesterol
Integrity of the blood–brain barrier is essential for the normal functioning of CNS. Its disruption contributes to the pathobiology of various inflammatory neurodegenerative disorders. We have shown that the HMG‐CoA reductase inhibitor (lovastatin) attenuated experimental autoimmune encephalomyelitis (EAE, an inflammatory disease of CNS) in rodents by inhibiting the infiltration of mononuclear cells into the CNS. Here, using an in vitro system, we report that lovastatin inhibits endothelial–monocyte cell interaction by down‐regulating the expression of vascular cell adhesion molecule‐1 and E‐selectin by inhibiting the phosphoinositide 3 kinase (PI3‐kinase)/protein kinase B (Akt)/nuclear factor‐kappa B (NF‐κB) pathway in endothelial cells. It inhibits tumor necrosis factor alpha (TNFα)‐induced PI3‐kinase, Akt and NF‐κB activation in these cells. Co‐transfection of constitutively active forms of PI3‐kinase and Akt reversed the lovastatin‐mediated inhibition of TNFα‐induced adhesion, as well as activation of NF‐κB, indicating the involvement of the PI3‐kinase/Akt pathway in the interaction of adhesion molecules and the process of adhesion. This study reports that lovastatin down‐regulates the pathway affecting the expression and interaction of adhesion molecules on endothelial cells, which in turn restricts the migration and infiltration of mononuclear cells thereby attenuating the pathogenesis of inflammatory diseases.