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.

Details

Title
Misoprostol treatment prevents hypoxia-induced cardiac dysfunction through a 14-3-3 and PKA regulatory motif on Bnip3
Author
Martens, Matthew D 1   VIAFID ORCID Logo  ; Seshadri Nivedita 2 ; Nguyen, Lucas 3 ; Chapman, Donald 3 ; Henson, Elizabeth S 4 ; Xiang, Bo 5 ; Falk, Landon 6 ; Mendoza Arielys 7   VIAFID ORCID Logo  ; Rattan Sunil 8   VIAFID ORCID Logo  ; Field, Jared T 1 ; Kawalec, Philip 1 ; Gibson, Spencer B 4 ; Keijzer, Richard 9 ; Saleem Ayesha 10   VIAFID ORCID Logo  ; Hatch, Grant M 5 ; Doucette, Christine A 2 ; Karch, Jason M 7 ; Dolinsky, Vernon W 5 ; Dixon, Ian M 8   VIAFID ORCID Logo  ; West, Adrian R 6   VIAFID ORCID Logo  ; Rampitsch Christof 11 ; Gordon, Joseph W 12   VIAFID ORCID Logo 

 University of Manitoba, Department of Human Anatomy and Cell Science, Winnipeg, Canada (GRID:grid.21613.37) (ISNI:0000 0004 1936 9609); Children’s Hospital Research Institute of Manitoba, Diabetes Research Envisioned and Accomplished in Manitoba (DREAM) Theme, Winnipeg, Canada (GRID:grid.460198.2) 
 Children’s Hospital Research Institute of Manitoba, Diabetes Research Envisioned and Accomplished in Manitoba (DREAM) Theme, Winnipeg, Canada (GRID:grid.460198.2); University of Manitoba, Department of Physiology and Pathophysiology, Winnipeg, Canada (GRID:grid.21613.37) (ISNI:0000 0004 1936 9609) 
 Children’s Hospital Research Institute of Manitoba, Diabetes Research Envisioned and Accomplished in Manitoba (DREAM) Theme, Winnipeg, Canada (GRID:grid.460198.2) 
 University of Manitoba, Department of Biochemistry and Medical Genetics, Winnipeg, Canada (GRID:grid.21613.37) (ISNI:0000 0004 1936 9609); CancerCare Manitoba, The Research Institute in Oncology and Hematology, Winnipeg, Canada (GRID:grid.419404.c) (ISNI:0000 0001 0701 0170) 
 Children’s Hospital Research Institute of Manitoba, Diabetes Research Envisioned and Accomplished in Manitoba (DREAM) Theme, Winnipeg, Canada (GRID:grid.460198.2); University of Manitoba, Department of Pharmacology and Therapeutics, Winnipeg, Canada (GRID:grid.21613.37) (ISNI:0000 0004 1936 9609) 
 University of Manitoba, Department of Physiology and Pathophysiology, Winnipeg, Canada (GRID:grid.21613.37) (ISNI:0000 0004 1936 9609); Children’s Hospital Research Institute of Manitoba, Biology of Breathing (BoB) Theme, Winnipeg, Canada (GRID:grid.460198.2) 
 Baylor College of Medicine, Department of Molecular Physiology and Biophysics, Cardiovascular Research Institute, Houston, USA (GRID:grid.39382.33) (ISNI:0000 0001 2160 926X) 
 University of Manitoba, Department of Physiology and Pathophysiology, Winnipeg, Canada (GRID:grid.21613.37) (ISNI:0000 0004 1936 9609); St. Boniface Research Centre, Institute for Cardiovascular Sciences, Winnipeg, Canada (GRID:grid.416356.3) (ISNI:0000 0000 8791 8068) 
 Children’s Hospital Research Institute of Manitoba, Biology of Breathing (BoB) Theme, Winnipeg, Canada (GRID:grid.460198.2); University of Manitoba, Department of Surgery, Winnipeg, Canada (GRID:grid.21613.37) (ISNI:0000 0004 1936 9609) 
10  Children’s Hospital Research Institute of Manitoba, Diabetes Research Envisioned and Accomplished in Manitoba (DREAM) Theme, Winnipeg, Canada (GRID:grid.460198.2); University of Manitoba, Faculty of Kinesiology and Recreation Management, Winnipeg, Canada (GRID:grid.21613.37) (ISNI:0000 0004 1936 9609) 
11  Morden Research & Development Centre, Agriculture and Agri-Food Canada, Morden, Canada (GRID:grid.55614.33) (ISNI:0000 0001 1302 4958) 
12  University of Manitoba, Department of Human Anatomy and Cell Science, Winnipeg, Canada (GRID:grid.21613.37) (ISNI:0000 0004 1936 9609); Children’s Hospital Research Institute of Manitoba, Diabetes Research Envisioned and Accomplished in Manitoba (DREAM) Theme, Winnipeg, Canada (GRID:grid.460198.2); University of Manitoba, College of Nursing, Winnipeg, Canada (GRID:grid.21613.37) (ISNI:0000 0004 1936 9609) 
Publication year
2021
Publication date
Dec 2021
Publisher
Springer Nature B.V.
e-ISSN
20414889
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2602349247
Copyright
© The Author(s) 2021. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.