Journal
REDOX BIOLOGY
Volume 48, Issue -, Pages -Publisher
ELSEVIER
DOI: 10.1016/j.redox.2021.102179
Keywords
Cardiomyocyte cGMP; FRET biosensor; Hypoxia; Ischemia/reperfusion; Phosphodiesterase
Categories
Funding
- Deutsche Forschungsgemeinschaft Research Unit 2060 cGMP Signaling in Cell Growth and Survival (grant FOR2060)
- Gertraud und Heinz-Rose Stiftung
- Deutsche Forschungsgemeinschaft Research Training Group cGMP: From Bedside to Bench [335549539/GRK 2381]
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This study reveals that hypoxia triggers rapid degradation of PDE3A protein via the autophagosomal-lysosomal pathway, leading to increased cGMP levels that prevent cell death and enhance protective effects of NO-GC activators.
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.
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