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

PLoS ONE. 2017 Apr 27;12(4):e0176243. eCollection 2017
Colleen Marie Bartman 1 , Yoshimasa Oyama 2 , Kelley Brodsky 3 , Ludmila Khailova 4 , Lori Walker 3 , Michael Koeppen 5 , Tobias Eckle 3
Colleen Marie Bartman 1 , Yoshimasa Oyama 2 , Kelley Brodsky 3 , Ludmila Khailova 4 , Lori Walker 3 , Michael Koeppen 5 , Tobias Eckle 3
+ et al

[No authors listed]

Author information
  • 1 Department of Cell and Developmental Biology, University of Colorado Denver School of Medicine, Aurora, CO, United States of America.
  • 2 Department of Anesthesiology and Intensive Care Medicine, Oita University Faculty of Medicine, Oita, Japan.
  • 3 Division of Cardiology, Department of Medicine, University of Colorado Denver School of Medicine, Aurora, CO, United States of America.
  • 4 Department of Anesthesiology, University of Colorado Denver School of Medicine, Aurora, CO, United States of America.
  • 5 Department of Anesthesiology, Ludwig Maximilian University of Munich, Munich, Germany.

摘要


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.