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- Title
Misoprostol treatment prevents hypoxia-induced cardiac dysfunction through a 14-3-3 and PKA regulatory motif on Bnip3.
- Authors
Martens, Matthew D.; Seshadri, Nivedita; Nguyen, Lucas; Chapman, Donald; Henson, Elizabeth S.; Xiang, Bo; Falk, Landon; Mendoza, Arielys; Rattan, Sunil; Field, Jared T.; Kawalec, Philip; Gibson, Spencer B.; Keijzer, Richard; Saleem, Ayesha; Hatch, Grant M.; Doucette, Christine A.; Karch, Jason M.; Dolinsky, Vernon W.; Dixon, Ian M.; West, Adrian R.
- Abstract
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.
- Publication
Cell Death & Disease, 2021, Vol 12, Issue 12, p1
- ISSN
2041-4889
- Publication type
Article
- DOI
10.1038/s41419-021-04402-3