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miR-199a-5p silencing regulates the unfolded protein response in chronic obstructive pulmonary disease and

Tidi Hassan1, Tomás P Carroll, Patrick G Buckley

  • 11 Respiratory Research Division, Department of Medicine, and.

American Journal of Respiratory and Critical Care Medicine
|December 5, 2013
PubMed
Abstract

Insights

MicroRNAs regulate the unfolded protein response in alpha-1 antitrypsin deficiency. Epigenetic silencing of miR-199a-5p in monocytes is linked to chronic obstructive pulmonary disease progression.

Area of Science:

  • Cellular and Molecular Biology
  • Pulmonary Medicine
  • Epigenetics

Background:

  • Alpha-1 antitrypsin (AAT) deficiency causes abnormal protein buildup, activating the unfolded protein response (UPR) in monocytes.
  • The role of microRNAs (miRNAs) in UPR and chronic obstructive pulmonary disease (COPD) pathogenesis remains unclear.

Purpose of the Study:

  • Investigate miRNA expression and function in MM and ZZ AAT-deficient monocytes.
  • Identify specific miRNAs that regulate the UPR in the context of AAT deficiency and COPD.

Main Methods:

  • Monocyte isolation from MM and ZZ individuals (asymptomatic vs. symptomatic).
  • miRNA expression profiling, pyrosequencing, quantitative PCR, and Western blotting.
  • Luciferase reporter assays to confirm miRNA-target interactions and functional studies using pre-miR/anti-miR.

Main Results:

  • Forty-three differentially expressed miRNAs identified; miR-199a-5p was significantly upregulated in asymptomatic ZZ monocytes.
  • Promoter hypermethylation of miR-199a-2 correlated with increased UPR markers (GRP78, ATF6, p50, p65) in symptomatic monocytes.
  • miR-199a-5p directly targets ATF6, p50, and p65, modulating UPR and cytokine expression.

Conclusions:

  • miR-199a-5p is a critical regulator of the UPR in AAT-deficient monocytes.
  • Epigenetic silencing of miR-199a-5p contributes to COPD pathogenesis by dysregulating the UPR.

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