14-3-3 Protein Protects Against Cardiac Endoplasmic Reticulum Stress (ERS) and ERS-Initiated Apoptosis in Experimental Diabetes

Flori R. Sari; Kenichi Watanabe; Rajarajan A. Thandavarayan; Meilei Harima; Shaosong Zhang; Anthony J. Muslin; Makoto Kodama; Yoshifusa Aizawa

doi:10.1254/jphs.10047FP

Full Papers

14-3-3 Protein Protects Against Cardiac Endoplasmic Reticulum Stress (ERS) and ERS-Initiated Apoptosis in Experimental Diabetes

Flori R. Sari, Kenichi Watanabe, Rajarajan A. Thandavarayan, Meilei Harima, Shaosong Zhang, Anthony J. Muslin, Makoto Kodama, Yoshifusa Aizawa

Author information

Flori R. Sari
Department of Clinical Pharmacology, Niigata University of Pharmacy and Applied Life Sciences, Japan
Department of Pharmacology, Faculty of Medicine and Health Sciences, Syarif Hidayatullah Jakarta, State Islamic University, Indonesia
Kenichi Watanabe
Department of Clinical Pharmacology, Niigata University of Pharmacy and Applied Life Sciences, Japan
Rajarajan A. Thandavarayan
Department of Clinical Pharmacology, Niigata University of Pharmacy and Applied Life Sciences, Japan
Meilei Harima
Department of Clinical Pharmacology, Niigata University of Pharmacy and Applied Life Sciences, Japan
Shaosong Zhang
Lightlab Imaging, Inc., USA
Anthony J. Muslin
Center for Cardiovascular Research, John Milliken Department of Internal Medicine, Washington University School of Medicine, USA
Makoto Kodama
First Department of Internal Medicine, Niigata University Graduate School of Medical and Dental Science, Japan
Yoshifusa Aizawa
First Department of Internal Medicine, Niigata University Graduate School of Medical and Dental Science, Japan

Keywords: 14-3-3 protein, diabetes mellitus, endoplasmic reticulum stress, apoptosis, glucose-regulated protein (GRP) 78

JOURNAL FREE ACCESS

2010 Volume 113 Issue 4 Pages 325-334

DOI https://doi.org/10.1254/jphs.10047FP

View "Advance Publication" version (July 13, 2010).

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Abstract

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.

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