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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.
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1 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)
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)
3 Children’s Hospital Research Institute of Manitoba, Diabetes Research Envisioned and Accomplished in Manitoba (DREAM) Theme, Winnipeg, Canada (GRID:grid.460198.2)
4 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)
5 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)
6 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)
7 Baylor College of Medicine, Department of Molecular Physiology and Biophysics, Cardiovascular Research Institute, Houston, USA (GRID:grid.39382.33) (ISNI:0000 0001 2160 926X)
8 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)
9 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)