Journal
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH
Volume 1803, Issue 4, Pages 452-467Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.bbamcr.2009.12.005
Keywords
Apoptosis; Statin; Caspase; Airway smooth muscle; Fibroblast; Mitochondria
Categories
Funding
- Canadian Institutes of Health Research (CIHR)
- GlaxoSmithKline
- Manitoba Institute of Child Health
- Canada Foundation
- CIHR/Canadian Lung Association/GlaxoSmithKline Postdoctoral fellowship
- National Training Program in Allergy and Asthma (NTPAA)
- Manitoba Health research Council (MHRC)
- MHRC/Manitoba Institute of Child Health (MICH)
- CIHR IMPACT Strategic Training Postdoctoral fellowship
- NTPAA
- MHRC
- MICH
- University of Manitoba
- Manitoba Blue Cross
- Dean Strategic Research Fund
- Faculty of Medicine at University of Manitoba
- GMH is a Canada Research Chair in Molecular Cardiolipin Metabolism
- Natural Sciences and Engineering Research Council of Canada (NSERC)
- DFG [SFB 773, GRK 1302]
- Deutsche Krebshilfe
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Statins inhibit 3-hydroxy-3-methyl-glutarylcoenzyme CoA (HMG-CoA) reductase, the proximal enzyme for cholesterol biosynthesis. They exhibit pleiotropic effects and are linked to health benefits for diseases including cancer and lung disease. Understanding their mechanism of action could point to new therapies, thus we investigated the response of primary cultured human airway mesenchymal cells, which play an effector role in asthma and chronic obstructive lung disease (COPD), to simvastatin exposure. Simvastatin induced apoptosis involving caspase-9, -3 and -7, but not caspase-8 in airway smooth muscle cells and fibroblasts. HMG-CoA inhibition did not alter cellular cholesterol content but did abrogate de novo cholesterol synthesis. Pro-apoptotic effects were prevented by exogenous mevalonate, geranylgeranyl pyrophosphate and farnesyl pyrophosphate, downstream products of HMG-CoA. Simvastatin increased expression of Bax, oligomerization of Bax and Bak, and expression of BH3-only p53-dependent genes, PUMA and NOXA. Inhibition of p53 and silencing of p53 unregulated modulator of apoptosis (PUMA) expression partly counteracted simvastatin-induced cell death, suggesting a role for p53-independent mechanisms. Simvastatin did not induce mitochondrial release of cytochrome c, but did promote release of inhibitor of apoptosis (IAP) proteins, Smac and Omi. Simvastatin also inhibited mitochondrial fission with the loss of mitochondrial Drp1, an essential component of mitochondrial fission machinery. Thus, simvastatin activates novel apoptosis pathways in lung mesenchymal cells involving p53. IAP inhibitor release, and disruption of mitochondrial fission. (C) 2009 Elsevier B.V. All rights reserved.
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