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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
2
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pubmed:dateCreated |
2005-2-4
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pubmed:abstractText |
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.
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pubmed:grant |
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pubmed:commentsCorrections |
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/3',5'-Cyclic-GMP Phosphodiesterases,
http://linkedlifedata.com/resource/pubmed/chemical/Akt1 protein, rat,
http://linkedlifedata.com/resource/pubmed/chemical/Calcineurin,
http://linkedlifedata.com/resource/pubmed/chemical/Cyclic GMP,
http://linkedlifedata.com/resource/pubmed/chemical/Cyclic GMP-Dependent Protein Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/Cyclic Nucleotide...,
http://linkedlifedata.com/resource/pubmed/chemical/DNA-Binding Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Extracellular Signal-Regulated MAP...,
http://linkedlifedata.com/resource/pubmed/chemical/NFATC Transcription Factors,
http://linkedlifedata.com/resource/pubmed/chemical/Nuclear Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Pde5a protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/Pde5a protein, rat,
http://linkedlifedata.com/resource/pubmed/chemical/Phosphatidylinositol 3-Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/Phosphodiesterase Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/Piperazines,
http://linkedlifedata.com/resource/pubmed/chemical/Protein-Serine-Threonine Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/Proto-Oncogene Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Proto-Oncogene Proteins c-akt,
http://linkedlifedata.com/resource/pubmed/chemical/Purines,
http://linkedlifedata.com/resource/pubmed/chemical/Sulfones,
http://linkedlifedata.com/resource/pubmed/chemical/Transcription Factors,
http://linkedlifedata.com/resource/pubmed/chemical/sildenafil
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pubmed:status |
MEDLINE
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pubmed:month |
Feb
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pubmed:issn |
1078-8956
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:volume |
11
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
214-22
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pubmed:dateRevised |
2010-11-18
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pubmed:meshHeading |
pubmed-meshheading:15665834-3',5'-Cyclic-GMP Phosphodiesterases,
pubmed-meshheading:15665834-Animals,
pubmed-meshheading:15665834-Animals, Newborn,
pubmed-meshheading:15665834-Blood Pressure,
pubmed-meshheading:15665834-Calcineurin,
pubmed-meshheading:15665834-Cardiomegaly,
pubmed-meshheading:15665834-Cyclic GMP,
pubmed-meshheading:15665834-Cyclic GMP-Dependent Protein Kinases,
pubmed-meshheading:15665834-Cyclic Nucleotide Phosphodiesterases, Type 5,
pubmed-meshheading:15665834-DNA-Binding Proteins,
pubmed-meshheading:15665834-Enzyme Activation,
pubmed-meshheading:15665834-Extracellular Signal-Regulated MAP Kinases,
pubmed-meshheading:15665834-Heart,
pubmed-meshheading:15665834-Hemodynamics,
pubmed-meshheading:15665834-Male,
pubmed-meshheading:15665834-Mice,
pubmed-meshheading:15665834-Mice, Inbred C57BL,
pubmed-meshheading:15665834-Mice, Transgenic,
pubmed-meshheading:15665834-Myocardium,
pubmed-meshheading:15665834-NFATC Transcription Factors,
pubmed-meshheading:15665834-Nuclear Proteins,
pubmed-meshheading:15665834-Phosphatidylinositol 3-Kinases,
pubmed-meshheading:15665834-Phosphodiesterase Inhibitors,
pubmed-meshheading:15665834-Piperazines,
pubmed-meshheading:15665834-Protein-Serine-Threonine Kinases,
pubmed-meshheading:15665834-Proto-Oncogene Proteins,
pubmed-meshheading:15665834-Proto-Oncogene Proteins c-akt,
pubmed-meshheading:15665834-Purines,
pubmed-meshheading:15665834-Rats,
pubmed-meshheading:15665834-Rats, Sprague-Dawley,
pubmed-meshheading:15665834-Sulfones,
pubmed-meshheading:15665834-Transcription Factors
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pubmed:year |
2005
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pubmed:articleTitle |
Chronic inhibition of cyclic GMP phosphodiesterase 5A prevents and reverses cardiac hypertrophy.
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pubmed:affiliation |
Division of Cardiology, Department of Medicine, Johns Hopkins Medical Institutions, Ross 835, 720 Rutland Avenue, Baltimore, Maryland 21205, USA.
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pubmed:publicationType |
Journal Article,
Research Support, U.S. Gov't, P.H.S.,
Research Support, Non-U.S. Gov't
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