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

Publication ,  Journal Article
Takimoto, E; Champion, HC; Li, M; Belardi, D; Ren, S; Rodriguez, ER; Bedja, D; Gabrielson, KL; Wang, Y; Kass, DA
Published in: Nat Med
February 2005

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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Published In

Nat Med

DOI

ISSN

1078-8956

Publication Date

February 2005

Volume

11

Issue

2

Start / End Page

214 / 222

Location

United States

Related Subject Headings

  • Transcription Factors
  • Sulfones
  • Sildenafil Citrate
  • Rats, Sprague-Dawley
  • Rats
  • Purines
  • Proto-Oncogene Proteins c-akt
  • Proto-Oncogene Proteins
  • Protein Serine-Threonine Kinases
  • Piperazines
 

Citation

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Takimoto, E., Champion, H. C., Li, M., Belardi, D., Ren, S., Rodriguez, E. R., … Kass, D. A. (2005). Chronic inhibition of cyclic GMP phosphodiesterase 5A prevents and reverses cardiac hypertrophy. Nat Med, 11(2), 214–222. https://doi.org/10.1038/nm1175
Takimoto, Eiki, Hunter C. Champion, Manxiang Li, Diego Belardi, Shuxun Ren, E Rene Rodriguez, Djahida Bedja, Kathleen L. Gabrielson, Yibin Wang, and David A. Kass. “Chronic inhibition of cyclic GMP phosphodiesterase 5A prevents and reverses cardiac hypertrophy.Nat Med 11, no. 2 (February 2005): 214–22. https://doi.org/10.1038/nm1175.
Takimoto E, Champion HC, Li M, Belardi D, Ren S, Rodriguez ER, et al. Chronic inhibition of cyclic GMP phosphodiesterase 5A prevents and reverses cardiac hypertrophy. Nat Med. 2005 Feb;11(2):214–22.
Takimoto, Eiki, et al. “Chronic inhibition of cyclic GMP phosphodiesterase 5A prevents and reverses cardiac hypertrophy.Nat Med, vol. 11, no. 2, Feb. 2005, pp. 214–22. Pubmed, doi:10.1038/nm1175.
Takimoto E, Champion HC, Li M, Belardi D, Ren S, Rodriguez ER, Bedja D, Gabrielson KL, Wang Y, Kass DA. Chronic inhibition of cyclic GMP phosphodiesterase 5A prevents and reverses cardiac hypertrophy. Nat Med. 2005 Feb;11(2):214–222.

Published In

Nat Med

DOI

ISSN

1078-8956

Publication Date

February 2005

Volume

11

Issue

2

Start / End Page

214 / 222

Location

United States

Related Subject Headings

  • Transcription Factors
  • Sulfones
  • Sildenafil Citrate
  • Rats, Sprague-Dawley
  • Rats
  • Purines
  • Proto-Oncogene Proteins c-akt
  • Proto-Oncogene Proteins
  • Protein Serine-Threonine Kinases
  • Piperazines