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

Colleen Marie Bartman, Yoshimasa Oyama, Kelley Brodsky, Ludmila Khailova, Lori Walker, Michael Koeppen, Tobias Eckle, Colleen Marie Bartman, Yoshimasa Oyama, Kelley Brodsky, Ludmila Khailova, Lori Walker, Michael Koeppen, Tobias Eckle

Abstract

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.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Fig 1. Studies of miR-21 regulation in…
Fig 1. Studies of miR-21 regulation in wiltype and Per2-/- mice after cardiac ischemic preconditioning.
Wildtype (A) or Per2-/- mice (B) were exposed to cardiac IPC, consisting of 4 x 5 minutes of ischemia followed by 5 minutes of reperfusion each, followed by a final reperfusion time of 120 min. Heart tissue was snap-frozen with clamps pre-cooled to the temperature of liquid nitrogen. Total RNA was isolated from murine heart tissue using Qiazol Reagent and separated into mRNA and miRNA components following manufactures instructions (SA-Biosciences, Qiagen). cDNA from miRNA was generated using miScript RT II kits (Qiagen) and transcript levels were determined by real-time RT-PCR (iCycler; Bio-Rad Laboratories Inc.; mean±SD, n = 3).
Fig 2. Diurnal expression of miR-21 in…
Fig 2. Diurnal expression of miR-21 in murine hearts and lungs.
Analysis of cardiac (A) or lung (B) mir-21 and Per2 levels from wildtype mice at Zeitgeber Time (ZT) 3 or ZT15. Total RNA was isolated from murine heart or lung tissue using Qiazol Reagent and separated into mRNA and miRNA components following manufactures instructions (SA-Biosciences, Qiagen). cDNA from miRNA was generated using miScript RT II kits (Qiagen) and transcript levels were determined by quantitative real-time RT-PCR (iCycler; Bio-Rad Laboratories Inc.; mean±SD, n = 3, p<0.05).
Fig 3. miR-21 expression in different cardiac…
Fig 3. miR-21 expression in different cardiac tissues at baseline and during hypoxia.
Fibroblasts or myocytes were isolated from C57BL6/J mouse hearts and endothelial cells isolated from C57/BL6 mice were purchased from Cell Biologics for analyzing miR-21 expression at baseline or hypoxic (1% oxygen) conditions. miRNA was isolated using RNeasy Mini Kit (Qiagen), cDNA was generated using miScript RT II kits (Qiagen), and transcript levels were determined by quantitative real-time RT-PCR (iCycler; Bio-Rad Laboratories Inc.). (A) Relative miR-21 expression levels in C57BL6/J mouse isolated cardiac fibroblasts, myocytes, and endothelia at baseline (mean±SD, n = 3, not significant). (B) miR-21 expression in cardiac fibroblasts subjected to normoxia or hypoxia for 6 h (mean±SD, n = 6, not significant). (C) miR-21 expression in cardiac myocytes subjected to normoxia or hypoxia for 1 h (mean±SD, n = 3, not significant). (D) miR-21 expression in cardiac endothelia subjected to normoxia or hypoxia for 6 h (mean±SD, n = 6, p<0.05). (E) miR-21 expression in human endothelia (HMEC-1) subjected to normoxia or hypoxia for 6 h (mean±SD, n = 6, p<0.05).
Fig 4. Glycolysis in miR-21 gain or…
Fig 4. Glycolysis in miR-21 gain or loss of function human endothelial cells.
(A) Knockdown confirmation in anti-mir-21 (loss of function, LOF) treated human endothelial cells (HMEC-1). (B-E) Glucose metabolism from control (miScript Inhibitor Neg. Control, scrambled [SCR]) and anti-mir-21 (LOF) treated HMEC-1. (F) Overexpression in miR-21Mimic (gain of function [GOF]) treated HMEC-1. (G-J) Glucose metabolism from control (miScript miRNA Mimic Neg. Control, SCR) and miR-21Mimic (GOF) treated human endothelial cells (HMEC-1). Cells were seeded at a density of 100,000 cells/well. Glycolysis assay was performed using glycolysis stress test kit from Seahorse Biosciences according to manufacturer’s protocol using the XF24 instrument. The extracellular acidification rate (ECAR) response to glucose, oligomycin and 2-DG was measured (mean±SD, n = 6, p<0.05).
Fig 5. Light elicited cardioprotection in wildtype…
Fig 5. Light elicited cardioprotection in wildtype and miR-21-/- mice.
(A-E) Mice underwent 60 min of ischemia and 120 min of reperfusion at room light (200LUX) or after exposure to 3 hours of intense light (10,000 LUX). Infarct sizes were measured by double staining with Evan’s blue and triphenyl-tetrazolium chloride. Infarct sizes are expressed as the percent of the area at risk (AAR) that underwent infarction. (A) Infarct sizes in wildtype or miR-21-/- mice at room light conditions (mean±SD, n = 4, p<0.05). (B, C) Infarct sizes in wildtype mice after exposure to intense light for 3 h compared to room light conditions. (mean±SD, n = 4, p<0.05). (C) Representative infarct staining in hearts from wildtype mice exposed to intense light or room light prior to in situ myocardial ischemia and reperfusion (blue, retrograde Evan’s blue staining; red and white, area at risk; white, infarcted tissue). (D, E) Infarct sizes in miR-21-/- mice exposed to intense light or room light prior to in situ myocardial ischemia followed by reperfusion (mean±SD, n = 4, not significant). (E) Representative infarct staining in hearts from miR-21-/- mice exposed to intense light or room light prior to in situ myocardial ischemia reperfusion (blue, retrograde Evan’s blue staining; red and white, area at risk; white, infarcted tissue).
Fig 6. Effects of intense light on…
Fig 6. Effects of intense light on miR-21 regulation in mice and human subjects.
(A-C) Wildtype mice were exposed to broad spectrum intense light (10,000 lux) for 7 days (LD 14:10) and compared to controls that were maintained at room light (200 lux, LD 14:10). Total RNA was isolated from murine hearts using Qiazol Reagent and separated into mRNA and miRNA components following manufactures instructions (SA-Biosciences, Qiagen). cDNA from miRNA was generated using miScript RT II kits (Qiagen) and miR-21 or Per2 transcript levels were determined by real-time RT-PCR (iCycler; Bio-Rad Laboratories Inc.; mean±SD, n = 3, p<0.05). (D-F) 7 Healthy human volunteers were exposed to 30 minutes of intense blue light (Square One Wake Up Light, NatureBright, Day-Light 10,000 Lux) in the morning at 8:30 AM on 5 consecutive days. A blood draw was performed before light exposure on the first day (8:30 AM) and 5 days after light exposure (9.00 AM). Plasma samples were analyzed for miR-21 levels and PFK (phosphofructokinase) activity (mean±SD, n = 7, p<0.05).
Fig 7. Proposed model of IPC or…
Fig 7. Proposed model of IPC or light induced miR-21 and glycolysis.
Both IPC and light can induce Per2 in human or murine tissues. In a Per2 dependent manner miR-21 and phosphofructokinase (PFK) are transcriptionally induced which finally leads to increased PFK activity, glycolytic capacity and cardioprotection.

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