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Systemic hypoxia is a common element in most perinatal emergencies and is a known driver of Bnip3 expression in the neonatal heart. Bnip3 plays a prominent role in the evolution of necrotic cell death, disrupting ER calcium homeostasis and initiating mitochondrial permeability transition (MPT). Emerging evidence suggests a cardioprotective role for the prostaglandin E1 analog misoprostol during periods of hypoxia, but the mechanisms for this protection are not completely understood. Using a combination of mouse and cell models, we tested if misoprostol is cardioprotective during neonatal hypoxic injury by altering Bnip3 function. Here we report that hypoxia elicits mitochondrial-fragmentation, MPT, reduced ejection fraction, and evidence of necroinflammation, which were abrogated with misoprostol treatment or Bnip3 knockout. Through molecular studies we show that misoprostol leads to PKA-dependent Bnip3 phosphorylation at threonine-181, and subsequent redistribution of Bnip3 from mitochondrial Opa1 and the ER through an interaction with 14-3-3 proteins. Taken together, our results demonstrate a role for Bnip3 phosphorylation in the regulation of cardiomyocyte contractile/metabolic dysfunction, and necroinflammation. Furthermore, we identify a potential pharmacological mechanism to prevent neonatal hypoxic injury. © 2021. The Author(s).


Matthew D Martens, Nivedita Seshadri, Lucas Nguyen, Donald Chapman, Elizabeth S Henson, Bo Xiang, Landon Falk, Arielys Mendoza, Sunil Rattan, Jared T Field, Philip Kawalec, Spencer B Gibson, Richard Keijzer, Ayesha Saleem, Grant M Hatch, Christine A Doucette, Jason M Karch, Vernon W Dolinsky, Ian M Dixon, Adrian R West, Christof Rampitsch, Joseph W Gordon. Misoprostol treatment prevents hypoxia-induced cardiac dysfunction through a 14-3-3 and PKA regulatory motif on Bnip3. Cell death & disease. 2021 Nov 26;12(12):1105

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PMID: 34824192

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