Intense light-elicited upregulation of miR-21 facilitates glycolysis and cardioprotection through Per2-dependent mechanisms

PLoS One. 2017 Apr 27;12(4):e0176243. doi: 10.1371/journal.pone.0176243. eCollection 2017.


A wide search for ischemic preconditioning (IPC) mechanisms of cardioprotection identified the light elicited circadian rhythm protein Period 2 (Per2) to be cardioprotective. Studies on cardiac metabolism found a key role for light elicited Per2 in mediating metabolic dependence on carbohydrate metabolism. To profile Per2 mediated pathways following IPC of the mouse heart, we performed a genome array and identified 352 abundantly expressed and well-characterized Per2 dependent micro RNAs. One prominent result of our in silico analysis for cardiac Per2 dependent micro RNAs revealed a selective role for miR-21 in the regulation of hypoxia and metabolic pathways. Based on this Per2 dependency, we subsequently found a diurnal expression pattern for miR-21 with higher miR-21 expression levels at Zeitgeber time (ZT) 15 compared to ZT3. Gain or loss of function studies for miR-21 using miRNA mimics or miRNA inhibitors and a Seahorse Bioanalyzer uncovered a critical role of miR-21 for cellular glycolysis, glycolytic capacity, and glycolytic reserve. Exposing mice to intense light, a strategy to induce Per2, led to a robust induction of cardiac miR-21 tissue levels and decreased infarct sizes, which was abolished in miR-21-/- mice. Similarly, first translational studies in humans using intense blue light exposure for 5 days in healthy volunteers resulted in increased plasma miR-21 levels which was associated with increased phosphofructokinase activity, the rate-limiting enzyme in glycolysis. Together, we identified miR-21 as cardioprotective downstream target of Per2 and suggest intense light therapy as a potential strategy to enhance miR-21 activity and subsequent carbohydrate metabolism in humans.

Publication types

  • Clinical Trial

MeSH terms

  • Adult
  • Animals
  • Endothelial Cells / metabolism
  • Endothelial Cells / radiation effects
  • Female
  • Glycolysis / radiation effects*
  • Heart / radiation effects*
  • Humans
  • Ischemic Preconditioning
  • Light*
  • Lung / metabolism
  • Lung / radiation effects
  • Male
  • Mice
  • Mice, Inbred C57BL
  • MicroRNAs / genetics*
  • Myocardial Infarction / genetics
  • Myocardial Infarction / metabolism
  • Myocardial Infarction / pathology
  • Myocardium / metabolism*
  • Myocardium / pathology
  • Period Circadian Proteins / deficiency
  • Period Circadian Proteins / metabolism*
  • Phosphofructokinases / metabolism
  • Up-Regulation / radiation effects*
  • Young Adult


  • MIRN-21 microRNA, mouse
  • MicroRNAs
  • Period Circadian Proteins
  • Phosphofructokinases