Circadian rhythms are known to influence the severity of cardiac injury after myocardial infarction, but the pathophysiological mechanisms that underlie this association were unclear. A new study published in Nature reveals the role of the interaction between the circadian transcription factor BMAL1 and hypoxia-inducible factor 2α (HIF2α) in circadian-dependent cardioprotection after ischaemia–reperfusion injury (IRI), and highlights the potential of chronotherapeutic approaches for ischaemic heart disease.

In a mouse model of IRI that had the least severe degree of injury at zeitgeber time 8 (ZT8; 15:00) and the most severe injury at ZT20 (03:00), RNA sequencing analysis demonstrated distinct transcriptional profiles between the samples collected after 2 h of reperfusion at ZT8 and ZT20. Of note, BMAL1 transcriptional activity was upregulated at ZT8 compared with ZT20. Left ventricular biopsy samples from 73 patients undergoing elective aortic valve replacement surgery in the morning (median 10:32) or afternoon (median 17:15) were collected and subjected to 80 min of ischaemia by aortic cross-clamping. RNA sequencing analysis identified BMAL1 as the most downregulated gene among the morning cohort. The researchers also generated a mouse model of IRI with a cardiomyocyte-specific Bmal1 knockout, which showed reduced cardioprotection and depressed systolic function at ZT8 (but not at ZT20) compared with controls. Together, these mouse and human studies pinpoint the involvement of BMAL1 in modulating circadian rhythms in myocardial injury.