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Simvastatin Protects Neurons from Cytotoxicity by Up‐regulating Bcl‐2 mRNA and Protein: The Role of Endothelin‐1 on Bcl‐2 Expression
Author(s) -
Wood Wellington Gibson,
Butterick Tammy,
JohnsonAnuna Leslie,
Eckert Gunter,
Igbavboa Urule,
Muller Walter
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.716.7
Subject(s) - simvastatin , neuroprotection , gene knockdown , messenger rna , apoptosis , pharmacology , gene expression , biology , endothelin 1 , receptor , cancer research , medicine , gene , biochemistry
There is great interest albeit some controversy in the use of statins for the prevention or treatment of neurodegenerative diseases such as ischemic stroke, Alzheimer's disease and AIDS dementia. We have recently reported (JPET, 2005, 312,786–793; Neurobiol Dis, 2007, 25, 438–445) the novel findings that simvastatin in vivo stimulated brain gene and protein expression of Bcl‐2 and ET‐1 which have been shown to play pivotal roles in pro‐survival pathways. In in vitro studies (J Neurochem, 2007, 101, 77–86) we found that simvastatin prevented neuronal apoptosis which was mevalonate/cholesterol independent and that the neuroprotective effects of simvastatin were eliminated by suppression of Bcl‐2 expression. There is some evidence that ET‐1 may increase Bcl‐2 abundance. To determine if simvastatin induced ET‐1 influences Bcl‐2 regulation we examined the temporal levels of gene and protein expression of ET‐1 following drug treatment in primary mouse cortical neurons and SH‐SY5Y human neuroblastoma cells (5Y). Primary neurons incubated with simvastatin showed a significant increase in ET‐1 mRNA preceding the elevation of Bcl‐2 gene expression and protein levels. There was also a significant increase in ET‐1 protein in the conditioned media and lysate of mouse neurons. Exogenous ET‐1 incubated with 5Y cells significantly increased Bcl‐2 protein. The ET‐1 receptor antagonists BQ‐123 and BQ 788 inhibited the stimulatory effects of simvastatin on Bcl‐2 protein levels. These findings provide new insight into the potential use of statins which may have efficacy in neurodegenerative diseases in which programmed cell death has been implicated. Supported in part by NIH grants AG‐18357, AG‐23524 and the Department of Veterans Affairs.