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The BMAL1/HIF2A heterodimer modulates circadian variations of myocardial injury. | LitMetric

AI Article Synopsis

  • Acute myocardial infarction (AMI) is a major global health issue with increased severity and worse outcomes linked to morning onset cases, but the underlying molecular mechanisms for these circadian variations remain unclear.* -
  • Research identifies BMAL1, a key circadian transcription factor, as a regulator of myocardial injury, showing it works with HIF2A to influence heart damage based on the time of day.* -
  • Targeting the BMAL1/HIF2A/AREG pathway can provide significant heart protection, suggesting that aligning treatments with circadian rhythms could improve AMI management.*

Article Abstract

Acute myocardial infarction stands as a prominent cause of morbidity and mortality worldwide. 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. However, the molecular mechanisms that govern circadian variations of myocardial injury remain unclear. Here, we show that BMAL1, 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), 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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10925443PMC
http://dx.doi.org/10.21203/rs.3.rs-3938716/v1DOI Listing

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