期刊
FREE RADICAL BIOLOGY AND MEDICINE
卷 90, 期 -, 页码 206-218出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.freeradbiomed.2015.11.024
关键词
HERPUD1; Oxidative stress; IP3 receptor; Cell death
资金
- CONICYT: FONDECYT [1120212, 11140470, 11130285, 3130749]
- FONDAP [15130011]
- National Institutes of Health [HL113167]
- CONICYT Chile
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [P01HL095070, R01HL113167] Funding Source: NIH RePORTER
Homocysteine-inducible, endoplasmic reticulum (ER) stress-inducible, ubiquitin-like domain member 1 (HERPUD1), an ER resident protein, is upregulated in response to ER stress and Ca2(+) homeostasis deregulation. HERPUD1 exerts cytoprotective effects in various models, but its role during oxidative insult remains unknown. The aim of this study was to investigate whether HERPUD1 contributes to cytoprotection in response to redox stress and participates in mediating stress-dependent signaling pathways. Our data showed that HERPUD1 protein levels increased in HeLa cells treated for 30 min with H2O2 or angiotensin II and in aortic tissue isolated from mice treated with angiotensin II for 3 weeks. Cell death was higher in HERPUD1 knockdown (sh-HERPUD1) HeLa cells treated with H2O2 in comparison with control (sh-Luc) HeLa cells. This effect was abolished by the intracellular Ca2(+) chelating agent BAPTA-AM or the inositol 1,4,5-trisphosphate receptor (ITPR) antagonist xestospongin B, suggesting that the response to H2O2 was dependent on intracellular Ca2(+) stores and the ITPR. Ca2(+) kinetics showed that sh-HERPUD1 HeLa cells exhibited greater and more sustained cytosolic and mitochondrial Ca2(+) increases than sh-Luc HeLa cells. This higher sensitivity of sh-HERPUD1 HeLa cells to H2O2 was prevented with the mitochondrial permeability transition pore inhibitor cyclosporine A. We concluded that the HERPUD1-mediated cytoprotective effect against oxidative stress depends on the ITPR and Ca2(+) transfer from the ER to mitochondria. (C) 2015 Elsevier Inc. All rights reserved.
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