Identification of a new target of miR-16, vacuolar protein sorting 4a

Neeta Adhikari, Weihua Guan, Brian Capaldo, Aaron J. Mackey, Marjorie Carlson, Sundaram Ramakrishnan, Dinesha Walek, Manu Gupta, Adam Mitchell, Peter Eckman, Ranjit John, Euan Ashley, Paul J. Barton, Jennifer L. Hall

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Abstract

Rationale: The rationale was to utilize a bioinformatics approach to identify miRNA binding sites in genes with single nucleotide mutations (SNPs) to discover pathways in heart failure (HF). Objective: The objective was to focus on the genes containing miRNA binding sites with miRNAs that were significantly altered in end-stage HF and in response to a left ventricular assist device (LVAD). Methods and Results: BEDTools v2.14.3 was used to discriminate SNPs within predicted 39UTR miRNA binding sites. A member of the miR-15/107 family, miR-16, was decreased in the circulation of end-stage HF patients and increased in response to a LVAD (p<0.001). MiR-16 decreased Vacuolar Protein Sorting 4a (VPS4a) expression in HEK 293T cells (p<0.01). The SNP rs16958754 was identified in the miR-15/107 family binding site of VPS4a which abolished direct binding of miR-16 to the 3′UTR of VPS4a (p<0.05). VPS4a was increased in the circulation of end-stage HF patients (p<0.001), and led to a decrease in the number of HEK 293T cells in vitro (p<0.001). Conclusions: We provide evidence that miR-16 decreases in the circulation of end-stage HF patients and increases with a LVAD. Modeling studies suggest that miR-16 binds to and decreases expression of VPS4a. Overexpression of VPS4a decreases cell number. Together, these experiments suggest that miR-16 and VPS4a expression are altered in end-stage HF and in response to unloading with a LVAD. This signaling pathway may lead to reduced circulating cell number in HF.

Original languageEnglish (US)
Article numbere101509
JournalPloS one
Volume9
Issue number7
DOIs
StatePublished - Jul 17 2014

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

Cite this

Adhikari, N., Guan, W., Capaldo, B., Mackey, A. J., Carlson, M., Ramakrishnan, S., Walek, D., Gupta, M., Mitchell, A., Eckman, P., John, R., Ashley, E., Barton, P. J., & Hall, J. L. (2014). Identification of a new target of miR-16, vacuolar protein sorting 4a. PloS one, 9(7), [e101509]. https://doi.org/10.1371/journal.pone.0101509