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BMAL1-HIF2A heterodimer modulates circadian variations of myocardial injury
Wei Ruan1,2, Tao Li3, In Hyuk Bang4
1Department of Anesthesiology, Critical Care and Pain Medicine, The University of Texas Health Science Center at Houston, McGovern Medical School, Houston, TX, USA. Wei.Ruan@uth.tmc.edu.
Insights
The core circadian transcription factor BMAL1 forms a complex with HIF2A, regulating myocardial injury in a diurnal manner. Targeting this pathway offers potential cardioprotection for heart attack patients.
Area of Science:
- Cardiovascular Biology
- Chronobiology
- Molecular Medicine
Background:
- Acute myocardial infarction is a major global health concern.
- Cardiac injury severity in myocardial infarction shows circadian variation, with worse outcomes in morning events.
- The molecular basis for these diurnal variations in heart injury is not well understood.
Purpose of the Study:
- To elucidate the molecular mechanisms driving circadian variations in myocardial injury.
- To investigate the role of the circadian transcription factor BMAL1 in regulating cardiac injury.
- To identify potential therapeutic targets for cardioprotection based on circadian rhythms.
Main Methods:
- Cryo-electron microscopy (cryo-EM) to determine the structure of the BMAL1-HIF2A-DNA complex.
- Investigated the interaction between BMAL1 and hypoxia-inducible factor 2 alpha (HIF2A).
- Identified amphiregulin (AREG) as a target gene of the BMAL1-HIF2A complex.
Main Results:
- BMAL1 forms a diurnal heterodimer with HIF2A, linking circadian rhythms and hypoxia signaling.
- The BMAL1-HIF2A complex enhances HIF2A transcriptional activity and protein stability.
- Amphiregulin (AREG) was identified as a rhythmic target critical for diurnal myocardial injury variations.
- Pharmacological targeting of the BMAL1-HIF2A-AREG pathway demonstrated circadian-phase-dependent cardioprotection.
Conclusions:
- A novel molecular mechanism involving BMAL1 and HIF2A explains circadian variations in myocardial injury.
- The BMAL1-HIF2A-AREG pathway is a key regulator of diurnal heart attack outcomes.
- Circadian clock-based pharmacological interventions show promise for treating ischemic heart disease.
Abstract:
Acute myocardial infarction is a leading cause of morbidity and mortality worldwide1. Clinical studies have shown that the severity of cardiac injury after myocardial infarction exhibits a circadian pattern, with larger infarcts and poorer outcomes in patients experiencing morning-onset events2-7. However, the molecular mechanisms underlying these diurnal variations remain unclear. Here we show that the core circadian transcription factor BMAL17-11 regulates circadian-dependent myocardial injury by forming a transcriptionally active heterodimer with a non-canonical partner-hypoxia-inducible factor 2 alpha (HIF2A)12-16-in a diurnal manner. To substantiate this finding, we determined the cryo-EM structure of the BMAL1-HIF2A-DNA complex, revealing structural rearrangements within BMAL1 that enable cross-talk between circadian rhythms and hypoxia signalling. BMAL1 modulates the circadian hypoxic response by enhancing the transcriptional activity of HIF2A and stabilizing the HIF2A protein. We further identified amphiregulin (AREG)16,17 as a rhythmic target of the BMAL1-HIF2A complex, critical for regulating daytime variations of myocardial injury. Pharmacologically targeting the BMAL1-HIF2A-AREG pathway provides cardioprotection, with maximum efficacy when aligned with the pathway's circadian phase. These findings identify a mechanism governing circadian variations of myocardial injury and highlight the therapeutic potential of clock-based pharmacological interventions for treating ischaemic heart disease.
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