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Rise of cGMP by partial phosphodiesterase-3A degradation enhances cardioprotection during hypoxia
- Source :
- Redox Biology, Vol 48, Iss, Pp 102179-(2021), Redox Biology
- Publication Year :
- 2021
- Publisher :
- Elsevier, 2021.
-
Abstract
- 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.<br />Graphical abstract Image 1
- Subjects :
- Programmed cell death
Medicine (General)
QH301-705.5
Clinical Biochemistry
Ischemia
Ischemia/reperfusion
Pharmacology
Biochemistry
FRET biosensor
chemistry.chemical_compound
R5-920
medicine
Cyclic adenosine monophosphate
Phosphodiesterase
Biology (General)
Hypoxia
Cyclic guanosine monophosphate
Cardioprotection
Chemistry
Organic Chemistry
Hypoxia (medical)
medicine.disease
Cardiomyocyte cGMP
Second messenger system
medicine.symptom
Research Paper
Subjects
Details
- Language :
- English
- ISSN :
- 22132317
- Volume :
- 48
- Database :
- OpenAIRE
- Journal :
- Redox Biology
- Accession number :
- edsair.doi.dedup.....dc492eb33f75a0501caabc41446ae29a