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Cell Death Discov. 2018 Sep 21;4:37. doi: 10.1038/s41420-018-0104-z. eCollection 2018.

Misoprostol regulates Bnip3 repression and alternative splicing to control cellular calcium homeostasis during hypoxic stress.

Author information

1
1Department of Human Anatomy and Cell Science, University of Manitoba, Winnipeg, Canada.
2
2Children's Hospital Research Institute of Manitoba, Winnipeg, Canada.
3
3Department of Pharmacology and Therapeutics, University of Manitoba, Winnipeg, Canada.
4
4The Diabetes Research Envisioned and Accomplished in Manitoba (DREAM) Theme, Children's Hospital Research Institute of Manitoba, Winnipeg, Canada.
5
5Department of Psychology, University of Manitoba, Winnipeg, Canada.
6
6Department of Biological Science, University of Manitoba, Winnipeg, Canada.
7
7Faculty of Health Disciplines, Athabasca University, Edmonton, Canada.
8
8College of Nursing, University of Manitoba, Winnipeg, Canada.
#
Contributed equally

Abstract

The cellular response to hypoxia involves the activation of a conserved pathway for gene expression regulated by the transcription factor complex called hypoxia-inducible factor (HIF). This pathway has been implicated in both the adaptive response to hypoxia and in several hypoxic-ischemic-related pathologies. Perinatal hypoxic injury, often associated with prematurity, leads to multi-organ dysfunction resulting in significant morbidity and mortality. Using a rodent model of neonatal hypoxia and several representative cell lines, we observed HIF1α activation and down-stream induction of the cell death gene Bnip3 in brain, large intestine, and heart which was mitigated by administration of the prostaglandin E1 analog misoprostol. Mechanistically, we determined that misoprostol inhibits full-length Bnip3 (Bnip3-FL) expression through PKA-mediated NF-κB (P65) nuclear retention, and the induction of pro-survival splice variants. We observed that the dominant small pro-survival variant of Bnip3 in mouse cells lacks the third exon (Bnip3ΔExon3), whereas human cells produce a pro-survival BNIP3 variant lacking exon 2 (BNIP3ΔExon2). In addition, these small Bnip3 splice variants prevent mitochondrial dysfunction, permeability transition, and necrosis triggered by Bnip3-FL by blocking calcium transfer from the sarco/endoplasmic reticulum to the mitochondria. Furthermore, misoprostol and Bnip3ΔExon3 promote nuclear calcium accumulation, resulting in HDAC5 nuclear export, NFAT activation, and adaptive changes in cell morphology and gene expression. Collectively, our data suggests that misoprostol can mitigate the potential damaging effects of hypoxia on multiple cell types by activating adaptive cell survival pathways through Bnip3 repression and alternative splicing.

Conflict of interest statement

The authors declare that they have no conflict of interest.

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