Sensory Neuropathy Affects Cardiac miRNA Expression Network Targeting IGF-1, SLC2a-12, EIF-4e, and ULK-2 mRNAs

Int J Mol Sci. 2019 Feb 25;20(4):991. doi: 10.3390/ijms20040991.

Abstract

Background: Here we examined myocardial microRNA (miRNA) expression profile in a sensory neuropathy model with cardiac diastolic dysfunction and aimed to identify key mRNA molecular targets of the differentially expressed miRNAs that may contribute to cardiac dysfunction.

Methods: Male Wistar rats were treated with vehicle or capsaicin for 3 days to induce systemic sensory neuropathy. Seven days later, diastolic dysfunction was detected by echocardiography, and miRNAs were isolated from the whole ventricles.

Results: Out of 711 known miRNAs measured by miRNA microarray, the expression of 257 miRNAs was detected in the heart. As compared to vehicle-treated hearts, miR-344b, miR-466b, miR-98, let-7a, miR-1, miR-206, and miR-34b were downregulated, while miR-181a was upregulated as validated also by quantitative real time polymerase chain reaction (qRT-PCR). By an in silico network analysis, we identified common mRNA targets (insulin-like growth factor 1 (IGF-1), solute carrier family 2 facilitated glucose transporter member 12 (SLC2a-12), eukaryotic translation initiation factor 4e (EIF-4e), and Unc-51 like autophagy activating kinase 2 (ULK-2)) targeted by at least three altered miRNAs. Predicted upregulation of these mRNA targets were validated by qRT-PCR.

Conclusion: This is the first demonstration that sensory neuropathy affects cardiac miRNA expression network targeting IGF-1, SLC2a-12, EIF-4e, and ULK-2, which may contribute to cardiac diastolic dysfunction. These results further support the need for unbiased omics approach followed by in silico prediction and validation of molecular targets to reveal novel pathomechanisms.

Keywords: capsaicin; heart; microRNA; network analysis; sensory neuropathy.

MeSH terms

  • Animals
  • Capsaicin / toxicity
  • Disease Models, Animal
  • Eukaryotic Initiation Factor-4E / genetics
  • Gene Expression Profiling
  • Gene Regulatory Networks
  • Glucose Transport Proteins, Facilitative / genetics
  • Heart Failure, Diastolic / etiology*
  • Heart Failure, Diastolic / genetics
  • Insulin-Like Growth Factor I / genetics
  • Male
  • MicroRNAs / genetics*
  • Polyneuropathies / chemically induced
  • Polyneuropathies / complications*
  • Protein-Serine-Threonine Kinases / genetics
  • Rats
  • Rats, Wistar

Substances

  • Eukaryotic Initiation Factor-4E
  • Glucose Transport Proteins, Facilitative
  • MicroRNAs
  • Slc2a12 protein, mouse
  • insulin-like growth factor-1, mouse
  • Insulin-Like Growth Factor I
  • Ulk2 protein, mouse
  • Protein-Serine-Threonine Kinases
  • Capsaicin