Misoprostol treatment prevents hypoxia-induced cardiac dysfunction through a 14-3-3 and PKA regulatory motif on Bnip3

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 (M...

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Autores principales:	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
Formato:	article
Lenguaje:	EN
Publicado:	Nature Publishing Group 2021
Materias:	Cytology QH573-671
Acceso en línea:	https://doaj.org/article/e1343dcb2c5b484c91d04a2bde3e5a8e
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spelling	oai:doaj.org-article:e1343dcb2c5b484c91d04a2bde3e5a8e2021-11-28T12:04:19ZMisoprostol treatment prevents hypoxia-induced cardiac dysfunction through a 14-3-3 and PKA regulatory motif on Bnip310.1038/s41419-021-04402-32041-4889https://doaj.org/article/e1343dcb2c5b484c91d04a2bde3e5a8e2021-11-01T00:00:00Zhttps://doi.org/10.1038/s41419-021-04402-3https://doaj.org/toc/2041-4889Abstract 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.Matthew D. MartensNivedita SeshadriLucas NguyenDonald ChapmanElizabeth S. HensonBo XiangLandon FalkArielys MendozaSunil RattanJared T. FieldPhilip KawalecSpencer B. GibsonRichard KeijzerAyesha SaleemGrant M. HatchChristine A. DoucetteJason M. KarchVernon W. DolinskyIan M. DixonAdrian R. WestChristof RampitschJoseph W. GordonNature Publishing GrouparticleCytologyQH573-671ENCell Death and Disease, Vol 12, Iss 12, Pp 1-16 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Cytology QH573-671
spellingShingle	Cytology QH573-671 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
description	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.
format	article
author	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
author_facet	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
author_sort	Matthew D. Martens
title	Misoprostol treatment prevents hypoxia-induced cardiac dysfunction through a 14-3-3 and PKA regulatory motif on Bnip3
title_short	Misoprostol treatment prevents hypoxia-induced cardiac dysfunction through a 14-3-3 and PKA regulatory motif on Bnip3
title_full	Misoprostol treatment prevents hypoxia-induced cardiac dysfunction through a 14-3-3 and PKA regulatory motif on Bnip3
title_fullStr	Misoprostol treatment prevents hypoxia-induced cardiac dysfunction through a 14-3-3 and PKA regulatory motif on Bnip3
title_full_unstemmed	Misoprostol treatment prevents hypoxia-induced cardiac dysfunction through a 14-3-3 and PKA regulatory motif on Bnip3
title_sort	misoprostol treatment prevents hypoxia-induced cardiac dysfunction through a 14-3-3 and pka regulatory motif on bnip3
publisher	Nature Publishing Group
publishDate	2021
url	https://doaj.org/article/e1343dcb2c5b484c91d04a2bde3e5a8e
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Misoprostol treatment prevents hypoxia-induced cardiac dysfunction through a 14-3-3 and PKA regulatory motif on Bnip3

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