Intense light-elicited upregulation of miR-21 facilitates glycolysis and cardioprotection through Per2-dependent mechanisms.
Intense light-elicited upregulation of miR-21 facilitates glycolysis and cardioprotection through Per2-dependent mechanisms.
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DOI：
10.1371/journal.pone.0176243
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Eckle T
中科院分区：
文献类型：
--
作者：
Bartman CM;Oyama Y;Brodsky K;Khailova L;Walker L;Koeppen M;Eckle T
对缺血预处理（IPC）心脏保护机制的广泛研究表明，光诱导的昼夜节律蛋白周期2（Per 2）具有心脏保护作用。心脏代谢的研究发现，光诱导的Per 2在介导碳水化合物代谢依赖性中起关键作用。为了分析小鼠心脏IPC后Per 2介导的通路，我们进行了基因组阵列，并鉴定了352个丰富表达和良好表征的Per 2依赖性microRNA。我们对心脏Per 2依赖性microRNA的计算机模拟分析的一个突出结果揭示了miR-21在缺氧和代谢途径调节中的选择性作用。基于这种Per 2依赖性，我们随后发现了miR-21的昼夜表达模式，与ZT 3相比，在Zeitgeber时间（ZT）15时miR-21的表达水平更高。使用miRNA模拟物或miRNA抑制剂和Seahorse生物分析仪进行的miR-21功能获得或丧失研究揭示了miR-21对细胞糖酵解、糖酵解能力和糖酵解储备的关键作用。将小鼠暴露于强光，这是一种诱导Per 2的策略，导致心脏miR-21组织水平的强烈诱导和梗死面积的减少，这在miR-21-/-小鼠中被消除。类似地，在健康志愿者中使用强蓝光暴露5天的人类首次翻译研究导致血浆miR-21水平增加，这与糖酵解中的限速酶磷酸果糖激酶活性增加相关。总之，我们确定了miR-21作为Per 2的心脏保护下游靶点，并建议强光疗法作为增强miR-21活性和随后人体碳水化合物代谢的潜在策略。
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.