Identification of a new target of miR-16, Vacuolar Protein Sorting 4a.

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 3'UTR 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.

• Authors: 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
• Journal: PloS one (PLoS One) Vol. 9 Issue 7 Pg. e101509 ( 2014) ISSN: 1932-6203 [Electronic] United States
• PMID: 25033200 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Validation Study)

Chemical References

• 3' Untranslated Regions
• Endosomal Sorting Complexes Required for Transport
• MIRN16 microRNA, human
• MicroRNAs
• Vacuolar Proton-Translocating ATPases
• ATPases Associated with Diverse Cellular Activities
• VPS4A protein, human

Topics

• 3' Untranslated Regions (genetics)
• ATPases Associated with Diverse Cellular Activities
• Aged
• Binding Sites (genetics)
• Cell Line
• Endosomal Sorting Complexes Required for Transport (biosynthesis, blood, genetics)
• Female
• HEK293 Cells
• Heart Failure (blood, genetics, therapy)
• Heart-Assist Devices
• Humans
• Male
• MicroRNAs (blood, genetics)
• Middle Aged
• Myocardium (pathology)
• Polymorphism, Single Nucleotide
• Vacuolar Proton-Translocating ATPases (biosynthesis, blood, genetics)