Marked disparity of microRNA modulation by cGMP-selective PDE5 versus PDE9 inhibitors in heart disease

JCI Insight. 2018 Aug 9;3(15):e121739. doi: 10.1172/jci.insight.121739.


MicroRNAs (miRs) posttranscriptionally regulate mRNA and its translation into protein, and are considered master controllers of genes modulating normal physiology and disease. There is growing interest in how miRs change with drug treatment, and leveraging this for precision guided therapy. Here we contrast 2 closely related therapies, inhibitors of phosphodiesterase type 5 or type 9 (PDE5-I, PDE9-I), given to mice subjected to sustained cardiac pressure overload (PO). Both inhibitors augment cyclic guanosine monophosphate (cGMP) to activate protein kinase G, with PDE5-I regulating nitric oxide (NO) and PDE9-I natriuretic peptide-dependent signaling. While both produced strong phenotypic improvement of PO pathobiology, they surprisingly showed binary differences in miR profiles; PDE5-I broadly reduces more than 120 miRs, including nearly half those increased by PO, whereas PDE9-I has minimal impact on any miR (P < 0.0001). The disparity evolves after pre-miR processing and is organ specific. Lastly, even enhancing NO-coupled cGMP by different methods leads to altered miR regulation. Thus, seemingly similar therapeutic interventions can be barcoded by profound differences in miR signatures, and reversing disease-associated miR changes is not required for therapy success.

Keywords: Cardiology; Cell Biology; Heart failure; Noncoding RNAs; Phosphodiesterases.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3',5'-Cyclic-AMP Phosphodiesterases / antagonists & inhibitors*
  • 3',5'-Cyclic-AMP Phosphodiesterases / metabolism
  • Animals
  • Cyclic GMP / metabolism
  • Cyclic GMP-Dependent Protein Kinases / metabolism
  • Cyclic Nucleotide Phosphodiesterases, Type 5 / metabolism
  • Disease Models, Animal
  • Heart Diseases / drug therapy*
  • Heart Diseases / etiology
  • Humans
  • Male
  • Mice
  • MicroRNAs / metabolism*
  • Natriuretic Peptides / metabolism
  • Nitric Oxide / metabolism
  • Phosphodiesterase 5 Inhibitors / pharmacology*
  • Phosphodiesterase 5 Inhibitors / therapeutic use
  • RNA Processing, Post-Transcriptional / drug effects*
  • Signal Transduction


  • MicroRNAs
  • Natriuretic Peptides
  • Phosphodiesterase 5 Inhibitors
  • Nitric Oxide
  • Cyclic GMP-Dependent Protein Kinases
  • 3',5'-Cyclic-AMP Phosphodiesterases
  • Cyclic Nucleotide Phosphodiesterases, Type 5
  • Cyclic GMP