W. Gibson Wood


Director of Graduate Studies, Department of Pharmacology, University of Minnesota School of Medicine, Associate Director for Education and Evaluation, Geriatric Research, Education and Clinical Center, VA Medical Center, Minneapolis, MN, USA

Abstract:

There is great interest albeit some controversy in the use of statins for treating neurodegenerative diseases such as ischemic stroke, Alzheimer disease and Parkinson disease. We reported the unexpected finding that simvastatin in vivo stimulated brain gene and protein expression of Bcl-2 and endothelin-1 both which have been shown to play pivotal roles in pro-survival pathways. We showed that simvastatin prevented neuronal apoptosis and neuroprotective effects of simvastatin were eliminated by suppression of Bcl-2 expression. Protective effects of simvastatin were independent of the mevalonate/isoprenoid/cholesterol pathway. There is some evidence that endothelin-1 alone may increase Bcl-2 abundance via a calcineurin/NFATc dependent pathway. Simvastatin increased endothelin-1 mRNA and protein levels and endothelin-1 stimulation of Bcl-2 was inhibited by endothelin-1 receptor antagonists. Simvastatin induced translocation of the transcription factor NFATc3/4 into the cell nucleus resulting in binding to the Bcl-2 promoter region. We provide novel evidence that simvastatin stimulates expression of Bcl-2 both in vivo and in vitro which is mediated by endothelin-1 but does not involve cholesterol or its precursors. These innovative findings provide one of the mechanisms for the purported neuroprotective actions of statins and provide new insight into the potential use of statins in neurodegenerative diseases in which programmed cell death has been implicated. Supported by National Institutes of Health grants AG-23524, AG-18357 and the Department of Veterans Affairs.