title: Airway mesenchymal cell death by mevalonate cascade inhibition: integration of autophagy, unfolded protein response and apoptosis focusing on Bcl2 family proteins.
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.
authors.affiliation: Department of Physiology, University of Manitoba, Canada; Manitoba Institute of Child Health, University of Manitoba, Canada; Department of Human Anatomy and Cell Science, University of Manitoba, Canada.
authors.forename: Saeid
authors.initials: S
authors.lastname: Ghavami
authors.affiliation: Department of Physiology, University of Manitoba, Canada; Manitoba Institute of Child Health, University of Manitoba, Canada.
authors.forename: Pawan
authors.initials: P
authors.lastname: Sharma
authors.affiliation: Department of Physiology, University of Manitoba, Canada; Manitoba Institute of Child Health, University of Manitoba, Canada.
authors.forename: Behzad
authors.initials: B
authors.lastname: Yeganeh
authors.affiliation: Department of Physiology, University of Manitoba, Canada; Manitoba Institute of Child Health, University of Manitoba, Canada.
authors.forename: Oluwaseun O
authors.initials: OO
authors.lastname: Ojo
authors.affiliation: Department of Physiology, University of Manitoba, Canada; Manitoba Institute of Child Health, University of Manitoba, Canada.
authors.forename: Aruni
authors.initials: A
authors.lastname: Jha
authors.affiliation: Department of Physiology, University of Manitoba, Canada; Manitoba Institute of Child Health, University of Manitoba, Canada.
authors.forename: Mark M
authors.initials: MM
authors.lastname: Mutawe
authors.affiliation: Department of Physiology, University of Manitoba, Canada; Manitoba Institute of Child Health, University of Manitoba, Canada.
authors.forename: Hessam H
authors.initials: HH
authors.lastname: Kashani
authors.affiliation: Dept. of Clinical & Experimental Medicine, Integrative Regenerative Med. (IGEN) Center, Linköping University, Sweden.
authors.forename: Marek J
authors.initials: MJ
authors.lastname: Los
authors.affiliation: Department of Human Anatomy and Cell Science, University of Manitoba, Canada.
authors.forename: Thomas
authors.initials: T
authors.lastname: Klonisch
authors.affiliation: Department of Internal Medicine, University of Manitoba, Canada.
authors.forename: Helmut
authors.initials: H
authors.lastname: Unruh
authors.affiliation: Department of Physiology, University of Manitoba, Canada; Manitoba Institute of Child Health, University of Manitoba, Canada; Department of Internal Medicine, University of Manitoba, Canada. Electronic address: ahalayk@cc.umanitoba.ca.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Halayko
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects*; D000071193:Autophagy-Related Protein 7; D000071183:Autophagy-Related Proteins; D001980:Bronchi / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D053471:Caspases, Initiator / Q000235:genetics / Q000378:metabolism; D002470:Cell Survival; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D008798:Mevalonic Acid / Q000494:pharmacology*; D051379:Mice; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D061251:Primary Cell Culture; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D019821:Simvastatin / Q000494:pharmacology; D044764:Ubiquitin-Activating Enzymes / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D044763:Ubiquitin-Conjugating Enzymes / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D056811:Unfolded Protein Response / Q000187:drug effects* / Q000235:genetics; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000172:deficiency / Q000235:genetics*; D051028:bcl-2-Associated X Protein / Q000172:deficiency / Q000235:genetics*
chemical_list: D000071183:Autophagy-Related Proteins; C494773:Bak1 protein, mouse; C494827:Bax protein, mouse; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D034741:RNA, Small Interfering; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D019821:Simvastatin; D044763:Ubiquitin-Conjugating Enzymes; C093516:CASP4 protein, human; D053471:Caspases, Initiator; C509349:ATG7 protein, human; D000071193:Autophagy-Related Protein 7; D044764:Ubiquitin-Activating Enzymes; C455621:ATG3 protein, human; D008798:Mevalonic Acid
keywords: Cell death; Endoplasmic reticulum stress; Fibroblast; Statin