Chronic inhibition of cyclic GMP phosphodiesterase 5A prevents and reverses cardiac hypertrophy

E Takimoto, HC Champion, M Li, D Belardi, S Ren… - Nature medicine, 2005 - nature.com
E Takimoto, HC Champion, M Li, D Belardi, S Ren, ER Rodriguez, D Bedja, KL Gabrielson…
Nature medicine, 2005nature.com
Sustained cardiac pressure overload induces hypertrophy and pathological remodeling,
frequently leading to heart failure. Genetically engineered hyperstimulation of guanosine
3′, 5′-cyclic monophosphate (cGMP) synthesis counters this response. Here, we show
that blocking the intrinsic catabolism of cGMP with an oral phosphodiesterase-5A (PDE5A)
inhibitor (sildenafil) suppresses chamber and myocyte hypertrophy, and improves in vivo
heart function in mice exposed to chronic pressure overload induced by transverse aortic …
Abstract
Sustained cardiac pressure overload induces hypertrophy and pathological remodeling, frequently leading to heart failure. Genetically engineered hyperstimulation of guanosine 3′,5′-cyclic monophosphate (cGMP) synthesis counters this response. Here, we show that blocking the intrinsic catabolism of cGMP with an oral phosphodiesterase-5A (PDE5A) inhibitor (sildenafil) suppresses chamber and myocyte hypertrophy, and improves in vivo heart function in mice exposed to chronic pressure overload induced by transverse aortic constriction. Sildenafil also reverses pre-established hypertrophy induced by pressure load while restoring chamber function to normal. cGMP catabolism by PDE5A increases in pressure-loaded hearts, leading to activation of cGMP-dependent protein kinase with inhibition of PDE5A. PDE5A inhibition deactivates multiple hypertrophy signaling pathways triggered by pressure load (the calcineurin/NFAT, phosphoinositide-3 kinase (PI3K)/Akt, and ERK1/2 signaling pathways). But it does not suppress hypertrophy induced by overexpression of calcineurin in vitro or Akt in vivo, suggesting upstream targeting of these pathways. PDE5A inhibition may provide a new treatment strategy for cardiac hypertrophy and remodeling.
nature.com