Biphasic Effect of Sildenafil on Energy Sensing is Mediated by Phosphodiesterases 2 and 3 in Adipocytes and Hepatocytes.

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  • Additional Information
    • Source:
      Publisher: MDPI Country of Publication: Switzerland NLM ID: 101092791 Publication Model: Electronic Cited Medium: Internet ISSN: 1422-0067 (Electronic) Linking ISSN: 14220067 NLM ISO Abbreviation: Int J Mol Sci Subsets: MEDLINE
    • Publication Information:
      Original Publication: Basel, Switzerland : MDPI, [2000-
    • Subject Terms:
      Adipocytes/*drug effects ; Adipocytes/*physiology ; Cyclic Nucleotide Phosphodiesterases, Type 2/*metabolism ; Cyclic Nucleotide Phosphodiesterases, Type 3/*metabolism ; Hepatocytes/*drug effects ; Hepatocytes/*physiology ; Signal Transduction/*drug effects ; Sildenafil Citrate/*pharmacology; Animals ; Cell Line ; Energy Metabolism/drug effects ; Humans ; Mice
    • Abstract:
      Sirt1 (Sirtuin 1), AMPK (AMP-activated protein kinase), and eNOS (endothelial nitric oxide synthase) modulate hepatic energy metabolism and inflammation and play a major role in the development of NASH. Cyclic nucleotide phosphodiesterases (PDEs) play an important role in signal transduction by modulating intracellular levels of cyclic nucleotides. We previously found the PDE5 inhibitor sildenafil to synergize with leucine and leucine-metformin combinations in preclinical studies of NASH and obesity. However, efficacy is diminished at higher sildenafil concentrations. Herein, we have successfully modeled the U-shaped sildenafil dose-response in vitro and utilized this model to assess potential mechanisms of this dose-response relationship. Adipocytes and liver cells were treated with leucine (0.5 mM) and different concentrations of sildenafil (1 nM to 100 µM). cAMP, cGMP, and P-AMPK protein expression were used to demonstrate the biphasic response for increasing concentrations of sildenafil. The reversal with higher sildenafil levels was blunted by PDE2 inhibition. These data indicate that sildenafil-mediated increases in cGMP inhibits PDE3 at lower concentrations, which increases cAMP. However, further increases in cGMP from higher sildenafil concentrations activate PDE2 and consequently decrease cAMP, which demonstrates crosstalk between cAMP and cGMP via PDE2, PDE3, and PDE5. These changes in cAMP concentration are further reflected in downstream effects, including AMPK activation.
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    • Contributed Indexing:
      Keywords: AMPK; NASH; PDE2; PDE3; PDE5; Sirt1; leucine; obesity; sildenafil
    • Accession Number:
      BW9B0ZE037 (Sildenafil Citrate)
      EC 3.1.4.17 (Cyclic Nucleotide Phosphodiesterases, Type 2)
      EC 3.1.4.17 (Cyclic Nucleotide Phosphodiesterases, Type 3)
    • Publication Date:
      Date Created: 20190629 Date Completed: 20191210 Latest Revision: 20200225
    • Publication Date:
      20231215
    • Accession Number:
      PMC6627652
    • Accession Number:
      10.3390/ijms20122992
    • Accession Number:
      31248114