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

TY - JOUR

T1 - Rise of cGMP by partial phosphodiesterase-3A degradation enhances cardioprotection during hypoxia

AU - Bork, Nadja

AU - Kuret, Anna

AU - Cruz Santos, Melanie

AU - Molina, Cristina

AU - Reiter, Beate

AU - Reichenspurner, Hermann

AU - Friebe, Andreas

AU - Skryabin, Boris V.

AU - Rozhdestvensky, Timofey S.

AU - Kuhn, Michaela

AU - Lukowski, Robert

AU - Nikolaev, Viacheslav

PY - 2021/12/1

Y1 - 2021/12/1

N2 - 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.

AB - 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.

U2 - 10.1016/j.redox.2021.102179

DO - 10.1016/j.redox.2021.102179

M3 - SCORING: Journal article

C2 - 34763298

VL - 48

JO - REDOX BIOL

JF - REDOX BIOL

SN - 2213-2317

M1 - 102179

ER -