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

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.

• Authors: Eiki Takimoto, Hunter C Champion, Manxiang Li, Diego Belardi, Shuxun Ren, E Rene Rodriguez, Djahida Bedja, Kathleen L Gabrielson, Yibin Wang, David A Kass
• Journal: Nature medicine (Nat Med) Vol. 11 Issue 2 Pg. 214-22 (Feb 2005) ISSN: 1078-8956 [Print] United States
• PMID: 15665834 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• DNA-Binding Proteins
• NFATC Transcription Factors
• Nuclear Proteins
• Phosphodiesterase Inhibitors
• Piperazines
• Proto-Oncogene Proteins
• Purines
• Sulfones
• Transcription Factors
• Sildenafil Citrate
• 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

Topics

• 3',5'-Cyclic-GMP Phosphodiesterases (antagonists & inhibitors, metabolism)
• Animals
• Animals, Newborn
• Blood Pressure (physiology)
• Calcineurin (metabolism)
• Cardiomegaly (drug therapy, enzymology, 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, pathology)
• NFATC Transcription Factors
• Nuclear Proteins (metabolism)
• Phosphatidylinositol 3-Kinases (metabolism)
• Phosphodiesterase Inhibitors (pharmacology, therapeutic use)
• Piperazines (pharmacology, therapeutic use)
• Protein Serine-Threonine Kinases (genetics, metabolism)
• Proto-Oncogene Proteins (genetics, metabolism)
• Proto-Oncogene Proteins c-akt
• Purines
• Rats
• Rats, Sprague-Dawley
• Sildenafil Citrate
• Sulfones
• Transcription Factors (metabolism)