BMAL1–HIF2A heterodimer modulates circadian variations of myocardial injury

Cardiac injury following myocardial infarction exhibits a circadian pattern, yet the underlying mechanism remains unclear. To elucidate genes governing circadian variation of myocardial injury, we conducted transcriptomic profiling of left-ventricular tissues from mice or humans experiencing myocardial injury at different daytimes. Through comprehensive analyses, including transgenic mouse models and functional studies, we identified BMAL1 as a pivotal transcription factor modulating diurnal variation of myocardial injury. Remarkably, we discovered that BMAL1 regulates circadian-dependent cardiac injury by forming a transcriptionally active heterodimer with HIF2A. Substantiating this finding, we determined the cryo-EM structure of the BMAL1/HIF2F/DNA complex, revealing a previously unknown capacity for structural rearrangement within BMAL1. Furthermore, we confirmed amphiregulin (AREG) as a transcriptional target of the BMAL1/HIF2A heterodimer, critical for modulating circadian variation of myocardial injury. Finally, targeting the BMAL1/HIF2A-AREG pathway via timed AREG administration or enhancing circadian rhythm pharmacologically offered significant cardioprotection, implicating this pathway in treating ischemic heart disease.