Apoptosis, autophagy and ER stress in mevalonate cascade inhibition-induced cell death of human atrial fibroblasts
| Autor: | Behzad Yeganeh, S I Rattan, Ryan H. Cunnington, Ian M.C. Dixon, Hessam H. Kashani, Parmeshwar P. Sharma, Andrew J. Halayko, Gerald L. Stelmack, Darren H. Freed, Krista L. Bathe, Saeid Ghavami, Thomas Klonisch |
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| Rok vydání: | 2012 |
| Předmět: |
Cancer Research
Programmed cell death Simvastatin Immunology Mevalonic Acid Apoptosis heart Endoplasmic Reticulum Caspase 7 03 medical and health sciences Cellular and Molecular Neuroscience 0302 clinical medicine Autophagy Humans Heart Atria Caspase Cells Cultured 030304 developmental biology 0303 health sciences biology Cell Death Myocardium unfolded protein response Cell Biology Fibroblasts Endoplasmic Reticulum Stress Caspase Inhibitors Caspases Initiator 3. Good health Cell biology Enzyme Activation 030220 oncology & carcinogenesis lysosome Autophagy Protein 5 biology.protein Unfolded protein response Unfolded Protein Response Original Article cardiac remodeling Signal transduction Hydroxymethylglutaryl-CoA Reductase Inhibitors Signal Transduction |
| Zdroj: | Cell Death & Disease |
| Popis: | 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitors (statins) are cholesterol-lowering drugs that exert other cellular effects and underlie their beneficial health effects, including those associated with myocardial remodeling. We recently demonstrated that statins induces apoptosis and autophagy in human lung mesenchymal cells. Here, we extend our knowledge showing that statins simultaneously induces activation of the apoptosis, autophagy and the unfolded protein response (UPR) in primary human atrial fibroblasts (hATF). Thus we tested the degree to which coordination exists between signaling from mitochondria, endoplasmic reticulum and lysosomes during response to simvastatin exposure. Pharmacologic blockade of the activation of ER-dependent cysteine-dependent aspartate-directed protease (caspase)-4 and lysosomal cathepsin-B and -L significantly decreased simvastatin-induced cell death. Simvastatin altered total abundance and the mitochondrial fraction of proapoptotic and antiapoptotic proteins, while c-Jun N-terminal kinase/stress-activated protein kinase mediated effects on B-cell lymphoma 2 expression. Chemical inhibition of autophagy flux with bafilomycin-A1 augmented simvastatin-induced caspase activation, UPR and cell death. In mouse embryonic fibroblasts that are deficient in autophagy protein 5 and refractory to autophagy induction, caspase-7 and UPR were hyper-induced upon treatment with simvastatin. These data demonstrate that mevalonate cascade inhibition-induced death of hATF manifests from a complex mechanism involving co-regulation of apoptosis, autophagy and UPR. Furthermore, autophagy has a crucial role in determining the extent of ER stress, UPR and permissiveness of hATF to cell death induced by statins. © 2012 Macmillan Publishers Limited. All rights reserved. |
| Databáze: | OpenAIRE |
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