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The BMAL1/HIF2A heterodimer modulates circadian variations of myocardial injury
Wei Ruan1,2,3, Tao Li4,3, Jaewoong Lee5,3
1Department of Anesthesiology, Critical Care and Pain Medicine, The University of Texas Health Science Center at Houston, McGovern Medical School, Houston, TX, 77030, USA.
Insights
The core circadian factor BMAL1, partnered with HIF2A, controls daily variations in heart attack injury. Targeting this BMAL1/HIF2A-AREG pathway offers cardioprotection, most effective when timed to the pathway's daily low.
Area of Science:
- Cardiovascular Biology
- Chronobiology
- Molecular Medicine
Background:
- Acute myocardial infarction is a leading global cause of death.
- Cardiac injury severity in myocardial infarction shows circadian variation, with worse outcomes in morning events.
- Molecular mechanisms underlying these circadian variations in myocardial injury are not well understood.
Purpose of the Study:
- To elucidate the molecular mechanisms behind circadian variations in myocardial injury.
- To identify key molecular players involved in the diurnal regulation of cardiac damage.
- To explore potential therapeutic targets for myocardial infarction based on circadian rhythms.
Main Methods:
- Investigated the role of the circadian transcription factor BMAL1 in myocardial injury.
- Utilized cryo-electron microscopy (cryo-EM) to determine the structure of the BMAL1/HIF2A/DNA complex.
- Identified and validated amphiregulin (AREG) as a target gene of the BMAL1/HIF2A heterodimer.
- Assessed the efficacy of pharmacological targeting of the BMAL1/HIF2A-AREG pathway in a cardioprotection model.
Main Results:
- BMAL1 orchestrates diurnal variability in myocardial injury.
- BMAL1 forms a diurnal heterodimer with HIF2A, linking circadian rhythms and hypoxia signaling.
- The BMAL1/HIF2A complex regulates amphiregulin (AREG) expression rhythmically.
- Pharmacological targeting of the BMAL1/HIF2A-AREG pathway demonstrated cardioprotection, with timing-dependent efficacy.
Conclusions:
- BMAL1 and HIF2A form a novel circadian heterodimer that governs diurnal variations in myocardial injury.
- The BMAL1/HIF2A-AREG pathway represents a new molecular mechanism for circadian regulation of cardiac damage.
- Targeting this pathway offers a promising strategy for circadian-based cardioprotection in myocardial infarction.
- Timing interventions to the circadian trough of the BMAL1/HIF2A-AREG pathway maximizes therapeutic benefit.
Abstract:
Acute myocardial infarction stands as a prominent cause of morbidity and mortality worldwide1-6. 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 infarctions7-14. However, the molecular mechanisms that govern circadian variations of myocardial injury remain unclear. Here, we show that BMAL114-20, 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.
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