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

摘要: 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 cGMP with an oral phosphodiesterase-5A (PDE5A) inhibitor (sildenafil) suppresses chamber myocyte hypertrophy, improves in vivo function mice exposed chronic induced by transverse aortic constriction. Sildenafil also reverses pre-established load while restoring normal. PDE5A increases pressure-loaded hearts, activation cGMP-dependent protein kinase inhibition PDE5A. deactivates multiple signaling pathways triggered (the calcineurin/NFAT, phosphoinositide-3 (PI3K)/Akt, ERK1/2 pathways). But it does not suppress overexpression calcineurin vitro or Akt vivo, suggesting upstream targeting these pathways. may provide a new treatment strategy for remodeling.