Rise of cGMP by partial phosphodiesterase-3A degradation enhances cardioprotection during hypoxia
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Rise of cGMP by partial phosphodiesterase-3A degradation enhances cardioprotection during hypoxia. / Bork, Nadja; Kuret, Anna; Cruz Santos, Melanie; Molina, Cristina; Reiter, Beate; Reichenspurner, Hermann; Friebe, Andreas; Skryabin, Boris V.; Rozhdestvensky, Timofey S.; Kuhn, Michaela; Lukowski, Robert; Nikolaev, Viacheslav.
In: REDOX BIOL, Vol. 48, 102179, 01.12.2021.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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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 -