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- Ghavami, Saeid (author)
Statin-triggered cell death in primary human lung mesenchyrnal cells involves p53-PUMA and release of Smac and Omi but not cytochrome c
- E-article/E-chapterEnglish2010
Publisher, publication year, extent ...
- Elsevier2010
Numbers
- LIBRIS-ID:22103638
- http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-86861uri
- urn:nbn:se:liu:diva-86861urn
- 10.1016/j.bbamcr.2009.12.005doi
Supplementary language notes
- Language:English
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- gratis
- Statins inhibit 3-hydroxy-3-methyl-glutarylcoenzyme CoA (HMG-CoA) reductase, the proximal enzyme forcholesterol biosynthesis. They exhibit pleiotropic effects and are linked to health benefits for diseasesincluding 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 aneffector role in asthma and chronic obstructive lung disease (COPD), to simvastatin exposure. Simvastatininduced apoptosis involving caspase-9, -3 and -7, but not caspase-8 in airway smooth muscle cells andfibroblasts. HMG-CoA inhibition did not alter cellular cholesterol content but did abrogate de novocholesterol synthesis. Pro-apoptotic effects were prevented by exogenous mevalonate, geranylgeranylpyrophosphate and farnesyl pyrophosphate, downstream products of HMG-CoA. Simvastatin increasedexpression of Bax, oligomerization of Bax and Bak, and expression of BH3-only p53-dependent genes, PUMAand NOXA. Inhibition of p53 and silencing of p53 unregulated modulator of apoptosis (PUMA) expressionpartly 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 ofapoptosis (IAP) proteins, Smac and Omi. Simvastatin also inhibited mitochondrial fission with the loss ofmitochondrial Drp1, an essential component of mitochondrial fission machinery. Thus, simvastatin activatesnovel apoptosis pathways in lung mesenchymal cells involving p53, IAP inhibitor release, and disruption ofmitochondrial fission.
Subject headings and genre
- Natural Sciences hsv
- Biological Sciences hsv
- Biochemistry and Molecular Biology hsv
- Naturvetenskap hsv
- Biologiska vetenskaper hsv
- Biokemi och molekylärbiologi hsv
- Cell Biology hsv
- Cellbiologi hsv
- Apoptosis Statin Caspase Airway smooth muscle Fibroblast Mitochondria
Added entries (persons, corporate bodies, meetings, titles ...)
- Mutawe, Mark M. (author)
- Hauff, Kristin (author)
- Stelmack, Gerald L. (author)
- Schaafsma, Dedmer (author)
- Sharma, Pawan (author)
- McNeill, Karol D. (author)
- Hynes, Tyler S. (author)
- Kung, Sam K. (author)
- Unruh, Helmut (author)
- Klonisch, Thomas (author)
- Hatch, Grant M. (author)
- Los, Marek Jan (author)
- Halayko, Andrew J. (author)
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- In:VärdpublikationBiochimica et Biophysica Acta1803:4, 452-4670006-3002
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