T-cadherin attenuates the PERK branch of the unfolded protein response and protects vascular endothelial cells from endoplasmic reticulum stress-induced apoptosis |
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| Authors: | Emmanouil Kyriakakis Maria Philippova Manjunath B Joshi Dennis Pfaff Valery Bochkov Taras Afonyushkin Paul Erne Therese J Resink |
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| Institution: | 1. Department of Biomedicine, Laboratory for Signal Transduction, Basel University Hospital, Hebelstrasse 20, CH 4031 Basel, Switzerland;2. Center for Biomolecular Medicine and Pharmacology, Department of Vascular Biology and Thrombosis Research, Medical University of Vienna, Schwarzspanierstrasse 17, 1090 Vienna, Austria;3. Division of Cardiology, Cantonal Hospital Luzern, CH 6000 Luzern, Switzerland;1. First Surgical Clinic Section, Department of Surgical, Oncological and Gastroenterological Sciences, University of Padua, Padua, Italy;2. Istituto di Ricerca Pediatrica-Città della Speranza, Padua, Italy;3. Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Padua, Italy;4. Venetian Oncology Institute, Padua, Italy;5. CNR-IENI, Padua, Italy;6. Department of Nanomedicine, The Methodist Hospital Research Institute, Houston, TX;1. Department of Pharmacology, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201-1559, USA;2. Center for Biomolecular Therapeutics, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201-1559, USA;3. Marlene Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201-1559, USA;4. Department of Pharmaceutical sciences, School of Pharmacy, University of Maryland, Baltimore, MD 21201, USA;5. Genomic Core Facility, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201-1559, USA;6. Department of Cancer Biology, Kimmel Cancer Center, Jefferson Medical College, Thomas Jefferson University, PA 19107, USA;3. Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan;4. Department of Metabolism and Atherosclerosis, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan;5. Institute for Protein Research, Osaka University, Suita, Osaka 565-0871, Japan;1. Physiology & Climatology, Indian Veterinary Research Institute, Izatnagar, Bareilly, Uttar Pradesh, India;2. Department of Animal Sciences and D.H. Barron Reproductive and Perinatal Biology Research Program, University of Florida, Gainesville, Florida, USA;3. Division of Livestock Economics, Statistics and Information Technology, Indian Veterinary Research Institute, Izatnagar, Bareilly, Uttar Pradesh, India |
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| Abstract: | Endoplasmic reticulum (ER) stress activated by perturbations in ER homeostasis induces the unfolded protein response (UPR) with chaperon Grp78 as the key activator of UPR signalling. The aim of UPR is to restore normal ER function; however prolonged or severe ER stress triggers apoptosis of damaged cells to ensure protection of the whole organism. Recent findings support an association of ER stress-induced apoptosis of vascular cells with cardiovascular pathologies. T-cadherin (T-cad), an atypical glycosylphosphatidylinositol-anchored member of the cadherin superfamily is upregulated in atherosclerotic lesions. Here we investigate the ability of T-cad to influence UPR signalling and endothelial cell (EC) survival during ER stress. EC were treated with a variety of ER stress-inducing compounds (thapsigargin, dithiothereitol, brefeldin A, tunicamycin, A23187 or homocysteine) and induction of ER stress validated by increases in levels of UPR signalling molecules Grp78 (glucose-regulated protein of 78 kDa), phospho-eIF2α (phosphorylated eukaryotic initiation factor 2α) and CHOP (C/EBP homologous protein). All compounds also increased T-cad mRNA and protein levels. Overexpression or silencing of T-cad in EC respectively attenuated or amplified the ER stress-induced increase in phospho-eIF2α, Grp78, CHOP and active caspases. Effects of T-cad-overexpression or T-cad-silencing on ER stress responses in EC were not affected by inclusion of either N-acetylcysteine (reactive oxygen species scavenger), LY294002 (phosphatidylinositol-3-kinase inhibitor) or SP6000125 (Jun N-terminal kinase inhibitor). The data suggest that upregulation of T-cad on EC during ER stress attenuates the activation of the proapoptotic PERK (PKR (double-stranded RNA-activated protein kinase)-like ER kinase) branch of the UPR cascade and thereby protects EC from ER stress-induced apoptosis. |
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