14-3-3 Protein Protects Against Cardiac Endoplasmic Reticulum Stress (ERS) and ERS-Initiated Apoptosis in Experimental Diabetes
Diabetic cardiomyopathy and nephropathy induce endoplasmic reticulum stress (ERS) and ERS-initiated apoptosis. The primary function of 14-3-3 protein is to inhibit apoptosis, but the roles of this protein in protecting against cardiac ERS and apoptosis in the diabetic heart are largely unknown. In t...
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doaj-c75603e33c0445d9b194189f8830cbc12020-11-25T01:11:34ZengElsevierJournal of Pharmacological Sciences1347-86132010-01-01113432533414-3-3 Protein Protects Against Cardiac Endoplasmic Reticulum Stress (ERS) and ERS-Initiated Apoptosis in Experimental DiabetesFlori R. Sari0Kenichi Watanabe1Rajarajan A. Thandavarayan2Meilei Harima3Shaosong Zhang4Anthony J. Muslin5Makoto Kodama6Yoshifusa Aizawa7Department of Clinical Pharmacology, Niigata University of Pharmacy and Applied Life Sciences, 265-1 Higashijima, Akiha-ku, Niigata 956-8603, Japan; Department of Pharmacology, Faculty of Medicine and Health Sciences, Syarif Hidayatullah Jakarta, State Islamic University, South Jakarta 15412, IndonesiaDepartment of Clinical Pharmacology, Niigata University of Pharmacy and Applied Life Sciences, 265-1 Higashijima, Akiha-ku, Niigata 956-8603, Japan; Corresponding author. watanabe@nupals.ac.jpDepartment of Clinical Pharmacology, Niigata University of Pharmacy and Applied Life Sciences, 265-1 Higashijima, Akiha-ku, Niigata 956-8603, JapanDepartment of Clinical Pharmacology, Niigata University of Pharmacy and Applied Life Sciences, 265-1 Higashijima, Akiha-ku, Niigata 956-8603, JapanLightlab Imaging, Inc., One Technology Park Drive, Westford, Massachusetts 01886, USACenter for Cardiovascular Research, John Milliken Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USAFirst Department of Internal Medicine, Niigata University Graduate School of Medical and Dental Science, 1-754 Asahimachi, Chuo-ku, Niigata 951-8510, JapanFirst Department of Internal Medicine, Niigata University Graduate School of Medical and Dental Science, 1-754 Asahimachi, Chuo-ku, Niigata 951-8510, JapanDiabetic cardiomyopathy and nephropathy induce endoplasmic reticulum stress (ERS) and ERS-initiated apoptosis. The primary function of 14-3-3 protein is to inhibit apoptosis, but the roles of this protein in protecting against cardiac ERS and apoptosis in the diabetic heart are largely unknown. In this study, we investigated the in vivo role of 14-3-3 protein in diabetic ERS and apoptosis using streptozotocin (STZ)-induced transgenic mice that showed cardiac-specific expression of a dominant negative (DN) 14-3-3η protein mutant. The expression levels of cardiac glucose-regulated protein (GRP) 78, inositol-requiring enzyme (Ire) 1α, and tumor necrosis factor receptor (TNFR)-associated factor (TRAF) 2 protein were significantly increased in the diabetic DN 14-3-3η mice compared with the diabetic wild-type. Moreover, cardiac apoptosis and the expression of CCAAT / enhancer binding protein homology protein (CHOP), caspase-12, and cleaved caspase-12 protein were significantly increased in the diabetic DN 14-3-3η mice. In conclusion, partial depletion of 14-3-3 protein in the diabetic heart exacerbates cardiac ERS and activates ERS-induced apoptosis pathways, at least in part, through the regulation of CHOP and caspase-12 via the Ire1α/TRAF2 pathway. The enhancement of 14-3-3 protein expression can be used as a novel protective therapy against ERS and ERS-initiated apoptosis in the diabetic heart. Keywords:: 14-3-3 protein, diabetes mellitus, endoplasmic reticulum stress, apoptosis, glucose-regulated protein (GRP) 78http://www.sciencedirect.com/science/article/pii/S1347861319308990 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Flori R. Sari Kenichi Watanabe Rajarajan A. Thandavarayan Meilei Harima Shaosong Zhang Anthony J. Muslin Makoto Kodama Yoshifusa Aizawa |
spellingShingle |
Flori R. Sari Kenichi Watanabe Rajarajan A. Thandavarayan Meilei Harima Shaosong Zhang Anthony J. Muslin Makoto Kodama Yoshifusa Aizawa 14-3-3 Protein Protects Against Cardiac Endoplasmic Reticulum Stress (ERS) and ERS-Initiated Apoptosis in Experimental Diabetes Journal of Pharmacological Sciences |
author_facet |
Flori R. Sari Kenichi Watanabe Rajarajan A. Thandavarayan Meilei Harima Shaosong Zhang Anthony J. Muslin Makoto Kodama Yoshifusa Aizawa |
author_sort |
Flori R. Sari |
title |
14-3-3 Protein Protects Against Cardiac Endoplasmic Reticulum Stress (ERS) and ERS-Initiated Apoptosis in Experimental Diabetes |
title_short |
14-3-3 Protein Protects Against Cardiac Endoplasmic Reticulum Stress (ERS) and ERS-Initiated Apoptosis in Experimental Diabetes |
title_full |
14-3-3 Protein Protects Against Cardiac Endoplasmic Reticulum Stress (ERS) and ERS-Initiated Apoptosis in Experimental Diabetes |
title_fullStr |
14-3-3 Protein Protects Against Cardiac Endoplasmic Reticulum Stress (ERS) and ERS-Initiated Apoptosis in Experimental Diabetes |
title_full_unstemmed |
14-3-3 Protein Protects Against Cardiac Endoplasmic Reticulum Stress (ERS) and ERS-Initiated Apoptosis in Experimental Diabetes |
title_sort |
14-3-3 protein protects against cardiac endoplasmic reticulum stress (ers) and ers-initiated apoptosis in experimental diabetes |
publisher |
Elsevier |
series |
Journal of Pharmacological Sciences |
issn |
1347-8613 |
publishDate |
2010-01-01 |
description |
Diabetic cardiomyopathy and nephropathy induce endoplasmic reticulum stress (ERS) and ERS-initiated apoptosis. The primary function of 14-3-3 protein is to inhibit apoptosis, but the roles of this protein in protecting against cardiac ERS and apoptosis in the diabetic heart are largely unknown. In this study, we investigated the in vivo role of 14-3-3 protein in diabetic ERS and apoptosis using streptozotocin (STZ)-induced transgenic mice that showed cardiac-specific expression of a dominant negative (DN) 14-3-3η protein mutant. The expression levels of cardiac glucose-regulated protein (GRP) 78, inositol-requiring enzyme (Ire) 1α, and tumor necrosis factor receptor (TNFR)-associated factor (TRAF) 2 protein were significantly increased in the diabetic DN 14-3-3η mice compared with the diabetic wild-type. Moreover, cardiac apoptosis and the expression of CCAAT / enhancer binding protein homology protein (CHOP), caspase-12, and cleaved caspase-12 protein were significantly increased in the diabetic DN 14-3-3η mice. In conclusion, partial depletion of 14-3-3 protein in the diabetic heart exacerbates cardiac ERS and activates ERS-induced apoptosis pathways, at least in part, through the regulation of CHOP and caspase-12 via the Ire1α/TRAF2 pathway. The enhancement of 14-3-3 protein expression can be used as a novel protective therapy against ERS and ERS-initiated apoptosis in the diabetic heart. Keywords:: 14-3-3 protein, diabetes mellitus, endoplasmic reticulum stress, apoptosis, glucose-regulated protein (GRP) 78 |
url |
http://www.sciencedirect.com/science/article/pii/S1347861319308990 |
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