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
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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3',5'-Cyclic-GMP Phosphodiesterases / antagonists & inhibitors
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3',5'-Cyclic-GMP Phosphodiesterases / metabolism*
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Animals
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Animals, Newborn
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Blood Pressure / physiology
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Calcineurin / metabolism
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Cardiomegaly / drug therapy*
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Cardiomegaly / enzymology
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Cardiomegaly / pathology
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Cyclic GMP / metabolism
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Cyclic GMP-Dependent Protein Kinases
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Cyclic Nucleotide Phosphodiesterases, Type 5
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DNA-Binding Proteins / metabolism
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Enzyme Activation
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Heart / drug effects*
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Hemodynamics
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Myocardium / enzymology
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Myocardium / pathology*
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NFATC Transcription Factors
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Nuclear Proteins / metabolism
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphodiesterase Inhibitors / pharmacology*
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Phosphodiesterase Inhibitors / therapeutic use
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Piperazines / pharmacology*
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Piperazines / therapeutic use
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-akt
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Purines
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Rats
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Rats, Sprague-Dawley
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Sildenafil Citrate
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Sulfones
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Transcription Factors / metabolism
Substances
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DNA-Binding Proteins
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NFATC Transcription Factors
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Nuclear Proteins
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Phosphodiesterase Inhibitors
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Piperazines
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Proto-Oncogene Proteins
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Purines
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Sulfones
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Transcription Factors
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Sildenafil Citrate
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Akt1 protein, rat
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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Cyclic GMP-Dependent Protein Kinases
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Extracellular Signal-Regulated MAP Kinases
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Calcineurin
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3',5'-Cyclic-GMP Phosphodiesterases
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Cyclic Nucleotide Phosphodiesterases, Type 5
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Pde5a protein, mouse
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Pde5a protein, rat
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Cyclic GMP