Statins impact primary embryonic mouse neural stem cell survival, cell death, and fate through distinct mechanisms
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2018 |
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| Erschienen: |
2018 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:13 |
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| Enthalten in: |
PloS one - 13(2018), 5 vom: 08., Seite e0196387 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Carson, Ross A [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 06.08.2018 Date Revised 14.12.2020 published: Electronic-eCollection Citation Status MEDLINE |
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| doi: |
10.1371/journal.pone.0196387 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM283854995 |
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| 100 | 1 | |a Carson, Ross A |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Statins impact primary embryonic mouse neural stem cell survival, cell death, and fate through distinct mechanisms |
| 264 | 1 | |c 2018 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 06.08.2018 | ||
| 500 | |a Date Revised 14.12.2020 | ||
| 500 | |a published: Electronic-eCollection | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a Hydroxymethylglutaryl-CoA Reductase Inhibitors |2 NLM | |
| 650 | 7 | |a Polyisoprenyl Phosphates |2 NLM | |
| 650 | 7 | |a RNA, Messenger |2 NLM | |
| 650 | 7 | |a Sesquiterpenes |2 NLM | |
| 650 | 7 | |a Srebf2 protein, mouse |2 NLM | |
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| 650 | 7 | |a Cholesterol |2 NLM | |
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| 650 | 7 | |a AGG2FN16EV |2 NLM | |
| 650 | 7 | |a Pravastatin |2 NLM | |
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| 700 | 1 | |a Rudine, Anthony C |e verfasserin |4 aut | |
| 700 | 1 | |a Tally, Serena J |e verfasserin |4 aut | |
| 700 | 1 | |a Franks, Alexis L |e verfasserin |4 aut | |
| 700 | 1 | |a Frahm, Krystle A |e verfasserin |4 aut | |
| 700 | 1 | |a Waldman, Jacob K |e verfasserin |4 aut | |
| 700 | 1 | |a Silswal, Neerupma |e verfasserin |4 aut | |
| 700 | 1 | |a Burale, Suban |e verfasserin |4 aut | |
| 700 | 1 | |a Phan, James V |e verfasserin |4 aut | |
| 700 | 1 | |a Chandran, Uma R |e verfasserin |4 aut | |
| 700 | 1 | |a Monaghan, A Paula |e verfasserin |4 aut | |
| 700 | 1 | |a DeFranco, Donald B |e verfasserin |4 aut | |
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