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

• DOI: 10.1038/s41420-018-0104-z
• Publication Date: 2018-09-21T11:24:10Z
• Authors: Jared T. Field; Matthew D. Martens; Wajihah Mughal; Yan Hai; Donald Chapman; Grant M. Hatch; Tammy L. Ivanco; William Diehl-Jones; Joseph W. Gordon
• Keywords: Hypoxia; NFAT

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