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

Nat Med. 2005 Feb;11(2):214-22. doi: 10.1038/nm1175. Epub 2005 Jan 23.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 3',5'-Cyclic-GMP Phosphodiesterases / antagonists & inhibitors
  • 3',5'-Cyclic-GMP Phosphodiesterases / metabolism*
  • Animals
  • Animals, Newborn
  • Blood Pressure / physiology
  • Calcineurin / metabolism
  • Cardiomegaly / drug therapy*
  • Cardiomegaly / enzymology
  • Cardiomegaly / pathology
  • Cyclic GMP / metabolism
  • Cyclic GMP-Dependent Protein Kinases
  • Cyclic Nucleotide Phosphodiesterases, Type 5
  • DNA-Binding Proteins / metabolism
  • Enzyme Activation
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Heart / drug effects*
  • Hemodynamics
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Myocardium / enzymology
  • Myocardium / pathology*
  • NFATC Transcription Factors
  • Nuclear Proteins / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphodiesterase Inhibitors / pharmacology*
  • Phosphodiesterase Inhibitors / therapeutic use
  • Piperazines / pharmacology*
  • Piperazines / therapeutic use
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt
  • Purines
  • Rats
  • Rats, Sprague-Dawley
  • Sildenafil Citrate
  • Sulfones
  • Transcription Factors / metabolism

Substances

  • DNA-Binding Proteins
  • NFATC Transcription Factors
  • Nuclear Proteins
  • Phosphodiesterase Inhibitors
  • Piperazines
  • Proto-Oncogene Proteins
  • Purines
  • Sulfones
  • Transcription Factors
  • Sildenafil Citrate
  • Phosphatidylinositol 3-Kinases
  • Akt1 protein, rat
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Cyclic GMP-Dependent Protein Kinases
  • Extracellular Signal-Regulated MAP Kinases
  • Calcineurin
  • 3',5'-Cyclic-GMP Phosphodiesterases
  • Cyclic Nucleotide Phosphodiesterases, Type 5
  • Pde5a protein, mouse
  • Pde5a protein, rat
  • Cyclic GMP