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

DOI Web Site 2 Citations 74 References
  • Sari Flori R.
    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
  • Watanabe Kenichi
    Department of Clinical Pharmacology, Niigata University of Pharmacy and Applied Life Sciences, Japan
  • Thandavarayan Rajarajan A.
    Department of Clinical Pharmacology, Niigata University of Pharmacy and Applied Life Sciences, Japan
  • Harima Meilei
    Department of Clinical Pharmacology, Niigata University of Pharmacy and Applied Life Sciences, Japan
  • Zhang Shaosong
    Lightlab Imaging, Inc., USA
  • Muslin Anthony J.
    Center for Cardiovascular Research, John Milliken Department of Internal Medicine, Washington University School of Medicine, USA
  • Kodama Makoto
    First Department of Internal Medicine, Niigata University Graduate School of Medical and Dental Science, Japan
  • Aizawa Yoshifusa
    First Department of Internal Medicine, Niigata University Graduate School of Medical and Dental Science, Japan

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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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