Abstract
Statins inhibit HMG-CoA reductase, the rate-limiting enzyme in the cholesterol biosynthesis pathway (CBP), and are used for the prevention of cardiovascular disease. The anti-inflammatory effects of statins may also provide therapeutic benefits and have led to their use in clinical trials for preeclampsia, a pregnancy-associated inflammatory condition, despite their current classification as category X (i.e. contraindicated during pregnancy). In the developing neocortex, products of the CBP play essential roles in proliferation and differentiation of neural stem-progenitor cells (NSPCs). To understand how statins could impact the developing brain, we studied effects of pravastatin and simvastatin on primary embryonic NSPC survival, proliferation, global transcription, and cell fate in vitro. We found that statins dose dependently decrease NSPC expansion by promoting cell death and autophagy of NSPCs progressing through the G1 phase of the cell cycle. Genome-wide transcriptome analysis demonstrates an increase in expression of CBP genes following pravastatin treatment, through activation of the SREBP2 transcription factor. Co-treatment with farnesyl pyrophosphate (FPP), a CBP metabolite downstream of HMG-CoA reductase, reduces SREBP2 activation and pravastatin-induced PARP cleavage. Finally, pravastatin and simvastatin differentially alter NSPC cell fate and mRNA expression during differentiation, through a non-CBP dependent pathway.
Highlights
Statins are inhibitors of HMG-CoA reductase, the rate-limiting enzyme in the synthesis of cholesterol, and have widespread clinical use for the treatment of hyperlipidemia and prevention of cardiovascular disease
In addition to examining immunofluorescence, we examined mRNA expression in differentiating neural stemprogenitor cells (NSPCs) treated with either 10μM pravastatin or 1μM simvastatin. Quantitative real-time PCR (qRT-PCR) analysis of differentiated NSPCs showed no difference in mRNA expression of the neuronal markers Tuj1 or Map2 in response to pravastatin (Fig 8A and 8B) or simvastatin (Fig 8E and 8F) treatment
We evaluated the effect of two statins with distinct pharmacokinetic properties on primary cultures of NSPCs derived from embryonic mouse cerebral cortex
Summary
Statins are inhibitors of HMG-CoA reductase, the rate-limiting enzyme in the synthesis of cholesterol, and have widespread clinical use for the treatment of hyperlipidemia and prevention of cardiovascular disease. The therapeutic benefit of statins extends beyond the cardiovascular. HD087288 (DBD, APM) a T32 training grant T32DK007052 from the National Institute of Diabetes and Digestive and Kidney Diseases (KAF), an ACS grant (RSG-09-054-0 1-GMC, APM), G. Mathers Charitable Foundation Award (APM), NIH T32-HD071834-01A1 (AR), NIH K12 HD052892-09 (AR), Magee-Womens Clinical Trainee Research Award (AR), the University of Pittsburgh Medical Center Department of Pediatrics Endowed Instructorship (AR). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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