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Myocardial remodeling is controlled by myocyte-targeted gene regulation of phosphodiesterase type 5.

Publication ,  Journal Article
Zhang, M; Takimoto, E; Hsu, S; Lee, DI; Nagayama, T; Danner, T; Koitabashi, N; Barth, AS; Bedja, D; Gabrielson, KL; Wang, Y; Kass, DA
Published in: J Am Coll Cardiol
December 7, 2010

OBJECTIVES: we tested the hypothesis that bi-directional, gene-targeted regulation of cardiomyocyte cyclic guanosine monophosphate-selective phosphodiesterase type 5 (PDE5) influences maladaptive remodeling in hearts subjected to sustained pressure overload. BACKGROUND: PDE5 expression is up-regulated in human hypertrophied and failing hearts, and its inhibition (e.g., by sildenafil) stimulates protein kinase G activity, suppressing and reversing maladaptive hypertrophy, fibrosis, and contractile dysfunction. Sildenafil is currently being clinically tested for the treatment of heart failure. However, researchers of new studies have questioned the role of myocyte PDE5 and protein kinase G (PKG) to this process, proposing alternative targets and mechanisms. METHODS: mice with doxycycline-controllable myocyte-specific PDE5 gene expression were generated (medium transgenic [TG] and high TG expression lines) and subjected to sustained pressure overload. RESULTS: Rest myocyte and heart function, histology, and molecular profiling were normal in both TG lines versus controls at 2 months of age. However, upon exposure to pressure overload (aortic banding), TG hearts developed more eccentric remodeling, maladaptive molecular signaling, depressed function, and amplified fibrosis with up-regulation of tissue growth factor signaling pathways. PKG activation was inhibited in TG myocytes versus controls. After establishing a severe cardiomyopathic state, high-TG mice received doxycycline to suppress PDE5 expression/activity only in myocytes. This in turn enhanced PKG activity and reversed all previously amplified maladaptive responses, despite sustained pressure overload. Sildenafil was also effective in this regard. CONCLUSIONS: these data strongly support a primary role of myocyte PDE5 regulation to myocardial pathobiology and PDE5 targeting therapy in vivo and reveal a novel mechanism of myocyte-orchestrated extracellular matrix remodeling via PDE5/cyclic guanosine monophosphate-PKG regulatory pathways.

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Published In

J Am Coll Cardiol

DOI

EISSN

1558-3597

Publication Date

December 7, 2010

Volume

56

Issue

24

Start / End Page

2021 / 2030

Location

United States

Related Subject Headings

  • Ventricular Remodeling
  • Signal Transduction
  • Myocytes, Cardiac
  • Monocytes
  • Mice
  • Humans
  • Gene Expression Regulation, Enzymologic
  • Cyclic Nucleotide Phosphodiesterases, Type 5
  • Cardiovascular System & Hematology
  • Animals
 

Citation

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Zhang, M., Takimoto, E., Hsu, S., Lee, D. I., Nagayama, T., Danner, T., … Kass, D. A. (2010). Myocardial remodeling is controlled by myocyte-targeted gene regulation of phosphodiesterase type 5. J Am Coll Cardiol, 56(24), 2021–2030. https://doi.org/10.1016/j.jacc.2010.08.612
Zhang, Manling, Eiki Takimoto, Steven Hsu, Dong I. Lee, Takahiro Nagayama, Thomas Danner, Norimichi Koitabashi, et al. “Myocardial remodeling is controlled by myocyte-targeted gene regulation of phosphodiesterase type 5.J Am Coll Cardiol 56, no. 24 (December 7, 2010): 2021–30. https://doi.org/10.1016/j.jacc.2010.08.612.
Zhang M, Takimoto E, Hsu S, Lee DI, Nagayama T, Danner T, et al. Myocardial remodeling is controlled by myocyte-targeted gene regulation of phosphodiesterase type 5. J Am Coll Cardiol. 2010 Dec 7;56(24):2021–30.
Zhang, Manling, et al. “Myocardial remodeling is controlled by myocyte-targeted gene regulation of phosphodiesterase type 5.J Am Coll Cardiol, vol. 56, no. 24, Dec. 2010, pp. 2021–30. Pubmed, doi:10.1016/j.jacc.2010.08.612.
Zhang M, Takimoto E, Hsu S, Lee DI, Nagayama T, Danner T, Koitabashi N, Barth AS, Bedja D, Gabrielson KL, Wang Y, Kass DA. Myocardial remodeling is controlled by myocyte-targeted gene regulation of phosphodiesterase type 5. J Am Coll Cardiol. 2010 Dec 7;56(24):2021–2030.
Journal cover image

Published In

J Am Coll Cardiol

DOI

EISSN

1558-3597

Publication Date

December 7, 2010

Volume

56

Issue

24

Start / End Page

2021 / 2030

Location

United States

Related Subject Headings

  • Ventricular Remodeling
  • Signal Transduction
  • Myocytes, Cardiac
  • Monocytes
  • Mice
  • Humans
  • Gene Expression Regulation, Enzymologic
  • Cyclic Nucleotide Phosphodiesterases, Type 5
  • Cardiovascular System & Hematology
  • Animals