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Marked Disparity of MicroRNA Modulation by cGMP-selective PDE5 versus PDE9 Inhibitors in Heart Disease

ABSTRACT: This SuperSeries is composed of the SubSeries listed below. Overall design: Refer to individual Series

INSTRUMENT(S): Illumina HiSeq 2500 (Mus musculus)

SUBMITTER: Kristen Kokkonen-Simon

PROVIDER: GSE112056 | GEO | 2018-08-09

SECONDARY ACCESSION(S): GSE112054 GSE112055S-EPMC6129132

REPOSITORIES: GEO

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

Kokkonen-Simon Kristen M KM Saberi Amir A Nakamura Taishi T Ranek Mark J MJ Zhu Guangshuo G Bedja Djahida D Kuhn Michaela M Halushka Marc K MK Lee Dong Ik DI Kass David A DA

JCI insight 20180809 15

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 cy ...[more]

PMID: 30089721

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

Project description: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.

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Marked Disparity of MicroRNA Modulation by cGMP-selective PDE5 versus PDE9 Inhibitors in Heart Disease

Project description:Marked Disparity of MicroRNA Modulation by cGMP-selective PDE5 versus PDE9 Inhibitors in Heart Disease

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