biostudies-literatureUnknownRuan WNIDDK NIH HHSNHLBI NIH HHSNIGMS NIH HHSAcute myocardial infarction stands as a prominent cause of morbidity and mortality worldwide^1-6. Clinical studies have demonstrated that the severity of cardiac injury following myocardial infarction exhibits a circadian pattern, with larger infarct sizes and poorer outcomes in patients experiencing morning onset myocardial infarctions^7-14. However, the molecular mechanisms that govern circadian variations of myocardial injury remain unclear. Here, we show that BMAL1^14-20, a core circadian transcription factor, orchestrates diurnal variability in myocardial injury. Unexpectedly, BMAL1 modulates circadian-dependent cardiac injury by forming a transcriptionally active heterodimer with a non-canonical partner, hypoxia-inducible factor 2 alpha (HIF2A)^6,21-23, in a diurnal manner. Substantiating this finding, we determined the cryo-EM structure of the BMAL1/HIF2A/DNA complex, revealing a previously unknown capacity for structural rearrangement within BMAL1, which enables the crosstalk between circadian rhythms and hypoxia signaling. Furthermore, we identified amphiregulin (AREG) as a rhythmic transcriptional target of the BMAL1/HIF2A heterodimer, critical for regulating circadian variations of myocardial injury. Finally, pharmacologically targeting the BMAL1/HIF2A-AREG pathway provides effective cardioprotection, with maximum efficacy when aligned with the pathway's circadian trough. Our findings not only uncover a novel mechanism governing the circadian variations of myocardial injury but also pave the way for innovative circadian-based treatment strategies, potentially shifting current treatment paradigms for myocardial infarction.Research squarers.3.rs-3938716https://www.ebi.ac.uk/biostudies/studies/S-EPMC10925443biostudies-literatureThe BMAL1/HIF2A heterodimer modulates circadian variations of myocardial injury.PMC10925443T32 GM135118R01 HL155950R01 HL154720R01 HL118266R01 GM144836R01 HL150401R01 DK122796R01 GM143587R01 HL169519R01 HL165748Muehlschlegel JDKim BZhang DLiang YLee JMa XRuan WNair RZhao ZTsai KLSeidman CEEltzschig HKYuan XWang YDeng WGorham JLi JAbebe AGLi LDeberge MZhou ZYoo SHSeidman JGLi TNarula JBang IHWang YYAranki SFAn YAfalseThe BMAL1/HIF2A heterodimer modulates circadian variations of myocardial injury.Acute myocardial infarction stands as a prominent cause of morbidity and mortality worldwide^1-6. Clinical studies have demonstrated that the severity of cardiac injury following myocardial infarction exhibits a circadian pattern, with larger infarct sizes and poorer outcomes in patients experiencing morning onset myocardial infarctions^7-14. However, the molecular mechanisms that govern circadian variations of myocardial injury remain unclear. Here, we show that BMAL1^14-20, a core circadian transcription factor, orchestrates diurnal variability in myocardial injury. Unexpectedly, BMAL1 modulates circadian-dependent cardiac injury by forming a transcriptionally active heterodimer with a non-canonical partner, hypoxia-inducible factor 2 alpha (HIF2A)^6,21-23, in a diurnal manner. Substantiating this finding, we determined the cryo-EM structure of the BMAL1/HIF2A/DNA complex, revealing a previously unknown capacity for structural rearrangement within BMAL1, which enables the crosstalk between circadian rhythms and hypoxia signaling. Furthermore, we identified amphiregulin (AREG) as a rhythmic transcriptional target of the BMAL1/HIF2A heterodimer, critical for regulating circadian variations of myocardial injury. Finally, pharmacologically targeting the BMAL1/HIF2A-AREG pathway provides effective cardioprotection, with maximum efficacy when aligned with the pathway's circadian trough. Our findings not only uncover a novel mechanism governing the circadian variations of myocardial injury but also pave the way for innovative circadian-based treatment strategies, potentially shifting current treatment paradigms for myocardial infarction.2024-01-01T00:00:00Z2024 Feb2025-04-19T22:03:42.929Z2025-04-19T22:03:42.929ZS-EPMC109254433846410310.21203/rs.3.rs-3938716/v1