Cardiac Period 2 in myocardial ischemia: Clinical implications of a light dependent protein

Bonney, Stephanie; Hughes, Kelly; Harter, Patrick N.; Mittelbronn, Michel; Walker, Lori A.; Eckle, Tobias

doi:10.1016/j.biocel.2012.12.022

Cited by 33 publications

(41 citation statements)

References 34 publications

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“…Our recent studies found an important role of light elicited Per2 in controlling glycolysis during myocardial ischemia [10, 12, 23]. To understand a potential role of miR-21 in glycolysis, we first performed loss of function (LOF) studies using miR-21 inhibitors.…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2017

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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.

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Section: Resultsmentioning

confidence: 99%

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

et al. 2017

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“…Peripheral tissues display oscillations in circadian rhythm protein expression similar to those of the brain, 12,13 likely through secreted signaling molecules (Figure 1). 10,14,15 …”

Section: Circadian Rhythms: ‘External Cues’ Vs ‘Internal Clock’mentioning

confidence: 99%

Circadian Rhythms in Anesthesia and Critical Care Medicine

Brainard

Gobel

Bartels

et al. 2014

Semin Cardiothorac Vasc Anesth

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The rotation of the earth and associated alternating cycles of light and dark–the basis of our circadian rhythms–are fundamental to human biology and culture. However, it was not until 1971 that researchers first began to describe the molecular mechanisms for the circadian system. During the last few years, groundbreaking research has revealed a multitude of circadian genes affecting a variety of clinical diseases, including diabetes, obesity, sepsis, cardiac ischemia, and sudden cardiac death. Anesthesiologists, in the operating room and intensive care units, manage these diseases on a daily basis as they significantly impact patient outcomes. Intriguingly, sedatives, anesthetics, and the ICU environment have all been shown to disrupt the circadian system in patients. In the current review we will discuss how newly acquired knowledge of circadian rhythms could lead to changes in clinical practice and new therapeutic concepts.

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“…The primary control of the circadian clock is located in the hypothalamic suprachiasmatic nuclei (SCN), which are used to synchronize peripheral clocks in organs and tissues [13], [14]. This synchronization is accomplished through a series of tightly regulated circadian genes such as Clock, Brain and muscle Arnt-like protein-1 (Bmal1)[15], Neuronal PAS domain protein 2 (Npas2), Cryptochrome (Cry1/2), and Period (Per1/2). Mutations in or knockout of these circadian genes lead to diverse pathophysiological disorders, including metabolic syndrome, obesity [16], premature aging [17], and abnormal sleep cycle [18].…”

Section: Introductionmentioning

confidence: 99%

Cardiac Per2 Functions as Novel Link between Fatty Acid Metabolism and Myocardial Inflammation during Ischemia and Reperfusion Injury of the Heart

et al. 2013

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Disruption of peripheral circadian rhyme pathways dominantly leads to metabolic disorders. Studies on circadian rhythm proteins in the heart indicated a role for Clock or Per2 in cardiac metabolism. In contrast to Clock−/−, Per2−/− mice have larger infarct sizes with deficient lactate production during myocardial ischemia. To test the hypothesis that cardiac Per2 represents an important regulator of cardiac metabolism during myocardial ischemia, we measured lactate during reperfusion in Per1−/−, Per2−/− or wildtype mice. As lactate measurements in whole blood indicated an exclusive role of Per2 in controlling lactate production during myocardial ischemia, we next performed gene array studies using various ischemia-reperfusion protocols comparing wildtype and Per2−/− mice. Surprisingly, high-throughput gene array analysis revealed dominantly lipid metabolism as the differentially regulated pathway in wildtype mice when compared to Per2−/−. In all ischemia-reperfusion protocols used, the enzyme enoyl-CoA hydratase, which is essential in fatty acid beta-oxidation, was regulated in wildtype animals only. Studies using nuclear magnet resonance imaging (NMRI) confirmed altered fatty acid populations with higher mono-unsaturated fatty acid levels in hearts from Per2−/− mice. Unexpectedly, studies on gene regulation during reperfusion revealed solely pro inflammatory genes as differentially regulated ‘Per2-genes’. Subsequent studies on inflammatory markers showed increasing IL-6 or TNFα levels during reperfusion in Per2−/− mice. In summary, these studies reveal an important role of cardiac Per2 for fatty acid metabolism and inflammation during myocardial ischemia and reperfusion, respectively.

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Cardiac Period 2 in myocardial ischemia: Clinical implications of a light dependent protein

Cited by 33 publications

References 34 publications

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

Circadian Rhythms in Anesthesia and Critical Care Medicine

Cardiac Per2 Functions as Novel Link between Fatty Acid Metabolism and Myocardial Inflammation during Ischemia and Reperfusion Injury of the Heart

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