Phosphodiesterase 5 inhibition blocks pressure overload-induced cardiac hypertrophy independent of the calcineurin pathway.
OBJECTIVE
Cyclic GMP (cGMP)-specific phosphodiesterase 5 (PDE5) inhibition by sildenafil (SIL) activates myocardial cGMP-dependent protein kinase G (PKG) and blunts cardiac hypertrophy. To date, the only documented target of PKG in myocardium is the serine-threonine phosphatase calcineurin (Cn), which is central to pathological cardiac hypertrophy. We tested whether Cn suppression is necessary in order to observe anti-hypertrophic effects of SIL.


RESULTS
Mice lacking the Cn-Abeta subunit (CnAbeta(-/-)) and wild-type (WT) controls were subjected to transverse aorta constriction (TAC) with or without SIL (200 mg/kg/day, p.o.) for 3 weeks. TAC-induced elevation of Cn expression and activity in WT was absent in CnAbeta(-/-) hearts, and the latter accordingly developed less cardiac hypertrophy (50 vs. 100% increase in heart weight/tibia length, P < 0.03) and chamber dilation. SIL remained effective in CnAbeta(-/-) mice, increasing PKG activity similarly as in WT, suppressing hypertrophy and fetal gene expression, and enhancing heart function without altering afterload. TAC-stimulated calcium-calmodulin kinase II, Akt, and glycogen synthase kinase 3beta in both groups (the first rising more in CnAbeta(-/-) hearts), and SIL also suppressed these similarly. Activation of extracellular signal-regulated kinase observed in WT-TAC but not CnAbeta(-/-) hearts was also suppressed by SIL.


CONCLUSIONS
PDE5A inhibition and its accompanying PKG activation blunt hypertrophy and improve heart function even without Cn activation. This occurs by its modulation of several alternative pathways which may result from concomitant distal targeting, or activity against a common proximal node.
Hsu
Steven
S
Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Ross-Building, Room 850, Baltimore, MD 21205, USA.
Nagayama
Takahiro
T
Koitabashi
Norimichi
N
Zhang
Manling
M
Zhou
Liye
L
Bedja
Djahida
D
Gabrielson
Kathleen L
KL
Molkentin
Jeffery D
JD
Kass
David A
DA
Takimoto
Eiki
E
D000818:Animals; D019703:Calcineurin / Q000502:physiology*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000502:physiology; D006332:Cardiomegaly / Q000517:prevention & control*; D017869:Cyclic GMP-Dependent Protein Kinases / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D038362:Glycogen Synthase Kinase 3 / Q000502:physiology; D000071679:Glycogen Synthase Kinase 3 beta; D006973:Hypertension / Q000150:complications*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D058986:Phosphodiesterase 5 Inhibitors; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D011687:Purines / Q000494:pharmacology; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000494:pharmacology*
D058986:Phosphodiesterase 5 Inhibitors; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D000068677:Sildenafil Citrate; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D017869:Cyclic GMP-Dependent Protein Kinases; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D048049:Extracellular Signal-Regulated MAP Kinases; D038362:Glycogen Synthase Kinase 3; D019703:Calcineurin