title: 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.affiliation: Division of Cardiology, Department of Medicine, Johns Hopkins Medical Institutions, Ross 835, 720 Rutland Avenue, Baltimore, Maryland 21205, USA.
authors.forename: Eiki
authors.initials: E
authors.lastname: Takimoto
authors.forename: Hunter C
authors.initials: HC
authors.lastname: Champion
authors.forename: Manxiang
authors.initials: M
authors.lastname: Li
authors.forename: Diego
authors.initials: D
authors.lastname: Belardi
authors.forename: Shuxun
authors.initials: S
authors.lastname: Ren
authors.forename: E Rene
authors.initials: ER
authors.lastname: Rodriguez
authors.forename: Djahida
authors.initials: D
authors.lastname: Bedja
authors.forename: Kathleen L
authors.initials: KL
authors.lastname: Gabrielson
authors.forename: Yibin
authors.initials: Y
authors.lastname: Wang
authors.forename: David A
authors.initials: DA
authors.lastname: Kass
mesh_terms: D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D001794:Blood Pressure / Q000502:physiology; D019703:Calcineurin / Q000378:metabolism; D006332:Cardiomegaly / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D006152:Cyclic GMP / Q000378:metabolism; D017869:Cyclic GMP-Dependent Protein Kinases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D004268:DNA-Binding Proteins / Q000378:metabolism; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006321:Heart / Q000187:drug effects*; D006439:Hemodynamics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009206:Myocardium / Q000201:enzymology / Q000473:pathology*; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D010879:Piperazines / Q000494:pharmacology* / Q000627:therapeutic use; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D011687:Purines; D051381:Rats; D017207:Rats, Sprague-Dawley; D000068677:Sildenafil Citrate; D013450:Sulfones; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D015106:3',5'-Cyclic-GMP Phosphodiesterases; D019703:Calcineurin; D006152:Cyclic GMP; D017869:Cyclic GMP-Dependent Protein Kinases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D004268:DNA-Binding Proteins; D048049:Extracellular Signal-Regulated MAP Kinases; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D019869:Phosphatidylinositol 3-Kinases; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D011687:Purines; D000068677:Sildenafil Citrate; D013450:Sulfones; D014157:Transcription Factors; C494920:Akt1 protein, rat; C517382:Pde5a protein, mouse; C517384:Pde5a protein, rat