Airway mesenchymal cell death by mevalonate cascade inhibition: Integration of autophagy, unfolded protein response and apoptosis focusing on Bcl2 family proteins

Ghavami, S; Sharma, P; Yeganeh, B; Ojo, OO; Jha, A; Mutawe, MM; Kashani, HH; Los, MJ; Klonisch, T; Unruh, H; Halayko, AJ

Airway mesenchymal cell death by mevalonate cascade inhibition: Integration of autophagy, unfolded protein response and apoptosis focusing on Bcl2 family proteins

Ghavami, S Sharma, P

Yeganeh, B Ojo, OO Jha, A Mutawe, MM Kashani, HH Los, MJ Klonisch, T Unruh, H Halayko, AJ

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Publication Type:: Journal Article
Citation:: Biochimica et Biophysica Acta - Molecular Cell Research, 2014, 1843 (7), pp. 1259 - 1271
Issue Date:: 2014-01-01

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Field	Value	Language
dc.contributor.author	Ghavami, S	en_US
dc.contributor.author	Sharma, P https://orcid.org/0000-0002-2904-2306	en_US
dc.contributor.author	Yeganeh, B	en_US
dc.contributor.author	Ojo, OO	en_US
dc.contributor.author	Jha, A	en_US
dc.contributor.author	Mutawe, MM	en_US
dc.contributor.author	Kashani, HH	en_US
dc.contributor.author	Los, MJ	en_US
dc.contributor.author	Klonisch, T	en_US
dc.contributor.author	Unruh, H	en_US
dc.contributor.author	Halayko, AJ	en_US
dc.date.available	2014-03-07	en_US
dc.date.issued	2014-01-01	en_US
dc.identifier.citation	Biochimica et Biophysica Acta - Molecular Cell Research, 2014, 1843 (7), pp. 1259 - 1271	en_US
dc.identifier.issn	0167-4889	en_US
dc.identifier.uri	http://hdl.handle.net/10453/115699
dc.description.abstract	HMG-CoA reductase, the proximal rate-limiting enzyme in the mevalonate pathway, is inhibited by statins. Beyond their cholesterol lowering impact, statins have pleiotropic effects and their use is linked to improved lung health. We have shown that mevalonate cascade inhibition induces apoptosis and autophagy in cultured human airway mesenchymal cells. Here, we show that simvastatin also induces endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) in these cells. We tested whether coordination of ER stress, autophagy and apoptosis determines survival or demise of human lung mesenchymal cells exposed to statin. We observed that simvastatin exposure activates UPR (activated transcription factor 4, activated transcription factor 6 and IRE1α) and caspase-4 in primary human airway fibroblasts and smooth muscle cells. Exogenous mevalonate inhibited apoptosis, autophagy and UPR, but exogenous cholesterol was without impact, indicating that sterol intermediates are involved with mechanisms mediating statin effects. Caspase-4 inhibition decreased simvastatin-induced apoptosis, whereas inhibition of autophagy by ATG7 or ATG3 knockdown significantly increased cell death. In BAX<sup>-/-</sup>/BAK<sup>-/-</sup> murine embryonic fibroblasts, simvastatin-triggered apoptotic and UPR events were abrogated, but autophagy flux was increased leading to cell death via necrosis. Our data indicate that mevalonate cascade inhibition, likely associated with depletion of sterol intermediates, can lead to cell death via coordinated apoptosis, autophagy, and ER stress. The interplay between these pathways appears to be principally regulated by autophagy and Bcl-2-family pro-apoptotic proteins. These findings uncover multiple mechanisms of action of statins that could contribute to refining the use of such agent in treatment of lung disease. © 2014 Elsevier B.V.	en_US
dc.relation.ispartof	Biochimica et Biophysica Acta - Molecular Cell Research	en_US
dc.relation.isbasedon	10.1016/j.bbamcr.2014.03.006	en_US
dc.subject.classification	Biochemistry & Molecular Biology	en_US
dc.subject.mesh	Bronchi	en_US
dc.subject.mesh	Fibroblasts	en_US
dc.subject.mesh	Myocytes, Smooth Muscle	en_US
dc.subject.mesh	Animals	en_US
dc.subject.mesh	Humans	en_US
dc.subject.mesh	Mice	en_US
dc.subject.mesh	Mevalonic Acid	en_US
dc.subject.mesh	Simvastatin	en_US
dc.subject.mesh	Ubiquitin-Activating Enzymes	en_US
dc.subject.mesh	Ubiquitin-Conjugating Enzymes	en_US
dc.subject.mesh	RNA, Small Interfering	en_US
dc.subject.mesh	Hydroxymethylglutaryl-CoA Reductase Inhibitors	en_US
dc.subject.mesh	Signal Transduction	en_US
dc.subject.mesh	Apoptosis	en_US
dc.subject.mesh	Cell Survival	en_US
dc.subject.mesh	Gene Expression Regulation	en_US
dc.subject.mesh	Autophagy	en_US
dc.subject.mesh	bcl-2 Homologous Antagonist-Killer Protein	en_US
dc.subject.mesh	bcl-2-Associated X Protein	en_US
dc.subject.mesh	Caspases, Initiator	en_US
dc.subject.mesh	Unfolded Protein Response	en_US
dc.subject.mesh	Primary Cell Culture	en_US
dc.subject.mesh	Autophagy-Related Proteins	en_US
dc.subject.mesh	Autophagy-Related Protein 7	en_US
dc.title	Airway mesenchymal cell death by mevalonate cascade inhibition: Integration of autophagy, unfolded protein response and apoptosis focusing on Bcl2 family proteins	en_US
dc.type	Journal Article
utslib.citation.volume	7	en_US
utslib.citation.volume	1843	en_US
utslib.for	0601 Biochemistry and Cell Biology	en_US
utslib.for	1108 Medical Microbiology	en_US
pubs.embargo.period	Not known	en_US
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Faculty of Science/School of Life Sciences
pubs.organisational-group	/University of Technology Sydney/Strength - CHT - Health Technologies
utslib.copyright.status	closed_access
pubs.issue	7	en_US
pubs.publication-status	Published	en_US
pubs.volume	1843	en_US

Abstract:

HMG-CoA reductase, the proximal rate-limiting enzyme in the mevalonate pathway, is inhibited by statins. Beyond their cholesterol lowering impact, statins have pleiotropic effects and their use is linked to improved lung health. We have shown that mevalonate cascade inhibition induces apoptosis and autophagy in cultured human airway mesenchymal cells. Here, we show that simvastatin also induces endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) in these cells. We tested whether coordination of ER stress, autophagy and apoptosis determines survival or demise of human lung mesenchymal cells exposed to statin. We observed that simvastatin exposure activates UPR (activated transcription factor 4, activated transcription factor 6 and IRE1α) and caspase-4 in primary human airway fibroblasts and smooth muscle cells. Exogenous mevalonate inhibited apoptosis, autophagy and UPR, but exogenous cholesterol was without impact, indicating that sterol intermediates are involved with mechanisms mediating statin effects. Caspase-4 inhibition decreased simvastatin-induced apoptosis, whereas inhibition of autophagy by ATG7 or ATG3 knockdown significantly increased cell death. In BAX^-/-/BAK^-/- murine embryonic fibroblasts, simvastatin-triggered apoptotic and UPR events were abrogated, but autophagy flux was increased leading to cell death via necrosis. Our data indicate that mevalonate cascade inhibition, likely associated with depletion of sterol intermediates, can lead to cell death via coordinated apoptosis, autophagy, and ER stress. The interplay between these pathways appears to be principally regulated by autophagy and Bcl-2-family pro-apoptotic proteins. These findings uncover multiple mechanisms of action of statins that could contribute to refining the use of such agent in treatment of lung disease. © 2014 Elsevier B.V.

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http://hdl.handle.net/10453/115699