The most dramatic feature of life on Earth is our adaptation to the cycle of day and night. Throughout
evolutionary time, almost all living organisms developed a molecular clock linked to the light-dark cycles of the
sun. In present time, we know that this molecular clock is crucial to maintain metabolic and physiological homeostasis.
Indeed, a dysregulated molecular clockwork is a major contributing factor to many metabolic diseases. In
fact, the time of onset of acute myocardial infarction exhibits a circadian periodicity and recent studies have
found that the light regulated circadian rhythm protein Period 2 (PER2) elicits endogenous cardioprotection from
ischemia. Manipulating the molecular clockwork may prove beneficial during myocardial ischemia in humans.
MicroRNAs are small non-coding RNA molecules capable of silencing messenger RNA (mRNA) targets. MicroRNA
dysregulation has been linked to cancer development, cardiovascular and neurological diseases, lipid
metabolism, and impaired immunity. Therefore, microRNAs are gaining interest as putative novel disease biomarkers
and therapeutic targets. To identify circadian microRNA-based cardioprotective pathways, a recent study
evaluated transcriptional changes of PER2 dependent microRNAs during myocardial ischemia. Out of 352 most
abundantly expressed microRNAs, miR-21 was amongst the top PER2 dependent microRNAs and was shown to
mediate PER2 elicited cardioprotection. Further analysis suggested circadian entrainment via intense light therapy
to be a potential strategy to enhance miR-21 activity in humans. In this review, we will focus on circadian microRNAs
in the context of cardioprotection and will highlight new discoveries, which could lead to novel therapeutic
concepts to treat myocardial ischemia.