This year’s Nobel Prize for Physiology or Medicine was awarded for work elucidating circadian rhythm molecular pathways. Greater understanding of circadian rhythm and its implications bring with it exciting discoveries. A role for circadian rhythm in ischemic cardiac protection has been identified in several studies
- The incidence of myocardial infarction (Ml) is known to be higher in the morning1 and there is a higher
rate of greater ischemic injury when the Ml occurs in the early morning2 . Additionally, the light elicited, circadian rhythm protein Per2, has been shown to have a cardioprotective role in ischemic cardiac events3 .
The cardiac metabolic response to ischemia is the source of tremendous damage to heart tissue. A lack of oxygen during cardiac ischemia, disrupts aerobic, oxidative phosphorylation resulting in an ATP deficit that leads to cell death. Products of glycolysis are shifted away from oxidative phosphorylation to the production of lactate – this shift results in damaging acidosis and less efficient ATP production. Studies on cardiac metabolism have found a key role for light induced expression increase of Per2 in the transcriptional induction of glycolytic enzymes, enhancing oxygen efficient glycolysis, making the heart better prepared to adapt to ischemia.4• 5 .
In a recent study, Dr. Colleen M. Bartman and her colleagues set out to clarify how PER2 exerts its cardioprotective effects on oxygen efficient pathways, to identify new therapeutic targets. To identify PER2- dependent miRNA elements of cardioprotective pathways, QIAGEN RF Kits were used to isolate miRNA from wildtype and PER2-/- mice and compare expression in miRNA PCR arrays. Of the 352 most abundantly expressed PER2-dependent miRNAs, miR-21 stood out.
To confirm miR-21 as a downstream PER2 target, wildtype and PER-/- mice were exposed to cardioprotective ischemic preconditioning (IPC – 4 cycles of 5 min. ischemia/5 min reperfusion) and heart miR-21 expression was analyzed via qPCR using QIAGEN miSCRIPT miRNA probes. IPC resulted in a 2.4- fold induction of miR-21 in wildtype mice, with no upregulation observed in Per2-/-mice. The group was then able to show an increase in miR-21 and PER2 with exposure to light. Exposing wildtype mice to
l4h/day of intense light increased cardiac miR-21 levels 6-fold and PER2 levels 4-fold. Next, wildtype controls or miR-21-/- mice were exposed to 3 hours of intense light prior to myocardial ischemia and reperfusion injury. Light exposure significantly reduced infarct sizes in wildtype controls but failed to induce cardioprotection in miR-21-/- mice. These finding suggests that miR-21 is a downstream target of light / PER2 in exerting cardioprotective effects.
In
humans, one week of intense light exposure in 8 human subjects increased their blood plasma miR-21 levels 3.5-fold and
phosphofructokinase (PFK) activity increased 49%. PFK expression was monitored
as it is the key regulatory enzyme in the glycolytic pathway. The significant
increase in PFK activity indicates miR- 21’s cardioprotective
effects could come from enhancement of glycolysis.
- Muller JE, Stone PH, Turi ZG, Rutherford JD, Czeisler CA, Parker C, et al. Circadian variation in the frequency of onset of acute myocardial infarction. N Engl J Med. 1985;313(21):1315–22
- Reiter R, Swingen C, Moore L, Henry TD, Traverse JH (2012) Circadian dependence of infarct size and left ventricular function after ST elevation myocardial infarction. Circ Res 110: 105–110
- Suarez‐Barrientos et al (2011) Circadian variations of infarct size in acute myocardial infarction. Heart 97: 970–976
- Gary D.Lopaschuk, Jagdip S. Jaswal (2012) A Role for Period 2 in Cardioprotection. Cell Met 16: 2-4
- Tobias Eckel et al (2012) Adora2b-elicited Per2 stabilization promotes a HIF-dependent metabolic switch crucial for myocardial adaptation to ischemia. Nature Medicine 18, 774–782
