Press Release | The circadian-hypoxia link in cardioprotection


This article by Dr. Tobias Eckle and Dr. Colleen Marie Bartman is published in Current Pharmaceutical Design, 2019. For further details, please visit:




Circadian rhythms are 24 hour cycles that are guided by exposure to alternating periods of day and night. These cycles affect biological activities in a variety of living organisms which are attuned to the circadian clock. A disturbance in circadian patterns is known to affect many biomolecular processes linked with metabolism and other physiological functions. Dr. Tobias Eckle and his team at the University of Colorado Anschutz Medical Campus have studied circadian rhythms in detail. Eckle’s recent research has specifically been directed towards identifying cellular adaptive mechanisms during hypoxic conditions such as myocardial ischemia – one of the leading causes of morbidity and mortality worldwide. The team has published their review in Current Pharmaceutical Design.

Adenosine signaling has been implicated in cardiac adaptation to limited oxygen availability. In a wide search for adenosine receptor elicited cardio-adaptive responses, Eckle’s group identified the circadian rhythm protein period 2 (PER2) as an adenosine signaling target. The researchers found that PER2 KO mice had larger infarct sizes and a limited ability to use carbohydrates for oxygen-efficient glycolysis compared to wild-type mice. This impairment was caused by a failure to stabilize the oxygen sensor hypoxia-inducible factor-1 alpha (HIF1A). Moreover, stabilization of PER2 in the heart by exposing mice to intense light resulted in the transcriptional induction of HIF1A regulated glycolytic enzymes and PER2-dependent cardio-protection from ischemia. Ongoing studies are attempting to elucidate the role of the light regulated circadian rhythm protein PER2 as an oxygen and metabolic sensor during conditions of limited oxygen availability.

In their comprehensive review article, Eckle et al. discuss an evolutionary link between light and oxygen sensing pathways in depth and provide an insight into molecular and cellular adaptation for resilience to adverse changes in the environment:

The appearance of sunlight and oxygen on earth were undoubtedly the most dramatic environmental changes during evolution. As a result, almost all organisms on this planet are equipped with light and oxygen sensing pathways. Notably, light sensing and oxygen sensing pathways in mammals are linked on a cellular level: Hypoxia inducible factor 1? (HIF1A), an evolutionarily conserved transcription factor enabling cellular adaptation to low oxygen availability, belongs to the same protein family as the light-regulated circadian core protein Period 2 (PER2). Both belong to the PAS domain superfamily of signal sensors for oxygen, light, or metabolism. As such, Hif1? messenger RNA levels cycle in a circadian manner in mouse cardiac tissue and rhythmic oxygen levels reset the circadian clock through HIF1A. “This evolutionary conserved relationship between light (circadian) and oxygen sensing pathways suggests a role for light elicited circadian rhythm proteins in disease states of low oxygen availability, such as myocardial ischemia,” states Eckle. He concludes that “Insights gained from an advanced understanding of this evolutionarily conserved relationship between light and oxygen sensing pathways, will ultimately provide new therapeutic opportunities to treat such diseases.” Read full press release to find out more at:


Press Release | A role for circadian enhancers to prevent myocardial injury in the perioperative setting

The article by Dr. Tobias Eckle et al. is published in Current Pharmaceutical Design, 2018


Innovative cardioprotective strategies are of imminent demand. Nonfatal myocardial ischemia (MI) poses a significant risk to patients undergoing major non-cardiac surgery and these non-cardiac surgeries account for around 8 million myocardial injuries per year. Considering perioperative MI is the most common major cardiovascular complication, identifying factors that lead to cardiac disease onset and finding solutions to prevent potential cardiac damage are of critical importance. Previous work revealed that anesthetics used in the perioperative setting alter cellular circadian biology and furthermore, a critical role for the circadian rhythm protein Period 2 (PER2) was revealed in promoting cardioprotection through metabolic pathway mediation. The current studies intended to answer this question: does anesthetic administration lead to increased susceptibility to MI, and if so, does targeting circadian PER2 provide a cardioprotective effect?

The starting point of the study was a screening test for the effects of frequently administered anesthetics on cardiac PER2. This screening demonstrated that only the benzodiazepine, midazolam, significantly downregulated PER2 levels in the heart tissue. Considering loss of PER2 is known to be detrimental during myocardial ischemia and reperfusion (IR)-injury, the study next addressed whether administration of midazolam prior to the occurrence of an MI would increase severity of such an incident. Using a well-established mouse model of myocardial IR-injury, the study team found that mice exposed to midazolam had an approximate 28.8% increase in infarct size compared to the control group. In agreement, Troponin-I levels were on average 198.9% greater in the mice given midazolam compared to the control mice. Indeed, mice administered midazolam were associated with deleterious consequences upon myocardial IR-injury.

The second part of the study sought to reverse the deleterious effects of midazolam when administered prior to myocardial ischemia. Recently, a large-scale screen identified nobiletin, a flavonoid from citrus peels, as a potent circadian PER2 enhancer. Not only was nobiletin found to increase cardiac PER2 and reduce infarct sizes by 47.4%, but nobiletin also abolished the deleterious effects of midazolam as demonstrated by a 28.9% decrease in infarct sizes and 55.4% decrease in Troponin-I levels in mice given both midazolam and nobiletin compared to mice given solely midazolam prior to myocardial ischemia. Furthermore, nobiletin provided cardioprotection in a PER2 dependent manner during IR-injury. This was demonstrated by nobiletin treatment prior to myocardial ischemia in mice with a genetic deletion of PER2, which revealed no cardioprotection.

This publication reports how midazolam mediated alterations of PER2 expression may have functional consequences during myocardial ischemia and identifies circadian biology as a potential consideration in translational studies and in the perioperative setting to prevent or treat myocardial ischemia.

Browse the Article at: The Circadian PER2 Enhancer Nobiletin Reverses the Deleterious Effects of Midazolam in Myocardial Ischemia and Reperfusion Injury

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