Rise of cGMP by partial phosphodiesterase-3A degradation enhances cardioprotection during hypoxia

3′,5′-cyclic guanosine monophosphate (cGMP) is a druggable second messenger regulating cell growth and survival in a plethora of cells and disease states, many of which are associated with hypoxia. For example, in myocardial infarction and heart failure (HF), clinical use of cGMP-elevating drugs imp...

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Autores principales:	Nadja I. Bork, Anna Kuret, Melanie Cruz Santos, Cristina E. Molina, Beate Reiter, Hermann Reichenspurner, Andreas Friebe, Boris V. Skryabin, Timofey S. Rozhdestvensky, Michaela Kuhn, Robert Lukowski, Viacheslav O. Nikolaev
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	Cardiomyocyte cGMP FRET biosensor Hypoxia Ischemia/reperfusion Phosphodiesterase Medicine (General) R5-920 Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/06f06ef82ac1467b9416c06fe88290d6
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spelling	oai:doaj.org-article:06f06ef82ac1467b9416c06fe88290d62021-11-10T04:25:39ZRise of cGMP by partial phosphodiesterase-3A degradation enhances cardioprotection during hypoxia2213-231710.1016/j.redox.2021.102179https://doaj.org/article/06f06ef82ac1467b9416c06fe88290d62021-12-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S2213231721003396https://doaj.org/toc/2213-23173′,5′-cyclic guanosine monophosphate (cGMP) is a druggable second messenger regulating cell growth and survival in a plethora of cells and disease states, many of which are associated with hypoxia. For example, in myocardial infarction and heart failure (HF), clinical use of cGMP-elevating drugs improves disease outcomes. Although they protect mice from ischemia/reperfusion (I/R) injury, the exact mechanism how cardiac cGMP signaling is regulated in response to hypoxia is still largely unknown. By monitoring real-time cGMP dynamics in murine and human cardiomyocytes using in vitro and in vivo models of hypoxia/reoxygenation (H/R) and I/R injury combined with biochemical methods, we show that hypoxia causes rapid but partial degradation of cGMP-hydrolyzing phosphodiesterase-3A (PDE3A) protein via the autophagosomal-lysosomal pathway. While increasing cGMP in hypoxia prevents cell death, partially reduced PDE3A does not change the pro-apoptotic second messenger 3′,5′-cyclic adenosine monophosphate (cAMP). However, it leads to significantly enhanced protective effects of clinically relevant activators of nitric oxide-sensitive guanylyl cyclase (NO-GC). Collectively, our mouse and human data unravel a new mechanism by which cardiac cGMP improves hypoxia-associated disease conditions.Nadja I. BorkAnna KuretMelanie Cruz SantosCristina E. MolinaBeate ReiterHermann ReichenspurnerAndreas FriebeBoris V. SkryabinTimofey S. RozhdestvenskyMichaela KuhnRobert LukowskiViacheslav O. NikolaevElsevierarticleCardiomyocyte cGMPFRET biosensorHypoxiaIschemia/reperfusionPhosphodiesteraseMedicine (General)R5-920Biology (General)QH301-705.5ENRedox Biology, Vol 48, Iss , Pp 102179- (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Cardiomyocyte cGMP FRET biosensor Hypoxia Ischemia/reperfusion Phosphodiesterase Medicine (General) R5-920 Biology (General) QH301-705.5
spellingShingle	Cardiomyocyte cGMP FRET biosensor Hypoxia Ischemia/reperfusion Phosphodiesterase Medicine (General) R5-920 Biology (General) QH301-705.5 Nadja I. Bork Anna Kuret Melanie Cruz Santos Cristina E. Molina Beate Reiter Hermann Reichenspurner Andreas Friebe Boris V. Skryabin Timofey S. Rozhdestvensky Michaela Kuhn Robert Lukowski Viacheslav O. Nikolaev Rise of cGMP by partial phosphodiesterase-3A degradation enhances cardioprotection during hypoxia
description	3′,5′-cyclic guanosine monophosphate (cGMP) is a druggable second messenger regulating cell growth and survival in a plethora of cells and disease states, many of which are associated with hypoxia. For example, in myocardial infarction and heart failure (HF), clinical use of cGMP-elevating drugs improves disease outcomes. Although they protect mice from ischemia/reperfusion (I/R) injury, the exact mechanism how cardiac cGMP signaling is regulated in response to hypoxia is still largely unknown. By monitoring real-time cGMP dynamics in murine and human cardiomyocytes using in vitro and in vivo models of hypoxia/reoxygenation (H/R) and I/R injury combined with biochemical methods, we show that hypoxia causes rapid but partial degradation of cGMP-hydrolyzing phosphodiesterase-3A (PDE3A) protein via the autophagosomal-lysosomal pathway. While increasing cGMP in hypoxia prevents cell death, partially reduced PDE3A does not change the pro-apoptotic second messenger 3′,5′-cyclic adenosine monophosphate (cAMP). However, it leads to significantly enhanced protective effects of clinically relevant activators of nitric oxide-sensitive guanylyl cyclase (NO-GC). Collectively, our mouse and human data unravel a new mechanism by which cardiac cGMP improves hypoxia-associated disease conditions.
format	article
author	Nadja I. Bork Anna Kuret Melanie Cruz Santos Cristina E. Molina Beate Reiter Hermann Reichenspurner Andreas Friebe Boris V. Skryabin Timofey S. Rozhdestvensky Michaela Kuhn Robert Lukowski Viacheslav O. Nikolaev
author_facet	Nadja I. Bork Anna Kuret Melanie Cruz Santos Cristina E. Molina Beate Reiter Hermann Reichenspurner Andreas Friebe Boris V. Skryabin Timofey S. Rozhdestvensky Michaela Kuhn Robert Lukowski Viacheslav O. Nikolaev
author_sort	Nadja I. Bork
title	Rise of cGMP by partial phosphodiesterase-3A degradation enhances cardioprotection during hypoxia
title_short	Rise of cGMP by partial phosphodiesterase-3A degradation enhances cardioprotection during hypoxia
title_full	Rise of cGMP by partial phosphodiesterase-3A degradation enhances cardioprotection during hypoxia
title_fullStr	Rise of cGMP by partial phosphodiesterase-3A degradation enhances cardioprotection during hypoxia
title_full_unstemmed	Rise of cGMP by partial phosphodiesterase-3A degradation enhances cardioprotection during hypoxia
title_sort	rise of cgmp by partial phosphodiesterase-3a degradation enhances cardioprotection during hypoxia
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/06f06ef82ac1467b9416c06fe88290d6
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Rise of cGMP by partial phosphodiesterase-3A degradation enhances cardioprotection during hypoxia

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