NDLI: Apoptosis, autophagy and ER stress in mevalonate cascade inhibition-induced cell death of human atrial fibroblasts.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Ghavami, S. Yeganeh, B. Stelmack, G. L. Kashani, H. H. Sharma, P. Cunnington, R. Rattan, S. Bathe, K. Klonisch, T. Dixon, I. M. C. Freed, D. H. Halayko, A. J.
Description	Country affiliation: Canada Author Affiliation: Ghavami S ( Department of Physiology, University of Manitoba, Winnipeg, Manitoba, Canada.)
Abstract	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.
File Format	HTM / HTML
e-ISSN	20414889
DOI	10.1038/cddis.2012.61
Journal	Cell Death and Disease
Volume Number	3
Language	English
Publisher	Nature Publishing Group
Publisher Date	2012-06-21
Publisher Place	Great Britain (UK)
Access Restriction	Open
Subject Keyword	Mevalonic Acid Research Support, Non-u.s. Gov't Cytology Hydroxymethylglutaryl-coa Reductase Inhibitors Endoplasmic Reticulum Autophagy Cell Death Fibroblasts Caspases, Initiator Caspase 7 Signal Transduction Heart Atria Simvastatin Cells, Cultured Pharmacology Metabolism Unfolded Protein Response Drug Effects Caspase Inhibitors Discipline Cell Biology Endoplasmic Reticulum Stress Myocardium Enzyme Activation Apoptosis
Content Type	Text
Resource Type	Article

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