Faculty, Staff and Student Publications

Language

English

Publication Date

5-1-2025

Journal

Nature

DOI

10.1038/s41586-025-08898-z

PMID

40269168

PMCID

PMC12095075

PubMedCentral® Posted Date

4-23-2025

PubMedCentral® Full Text Version

Post-print

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.

Keywords

ARNTL Transcription Factors, Basic Helix-Loop-Helix Proteins, Circadian Rhythm, Animals, Myocardial Infarction, Mice, Humans, Cryoelectron Microscopy, Male, Protein Multimerization, Models, Molecular, Myocardium, DNA, Cell Hypoxia, Protein Stability, Mice, Inbred C57BL, Hypoxia, Signal Transduction, Female, Endothelial PAS Domain-Containing Protein 1., Myocardial infarction, Translational research, Cryoelectron microscopy, Randomized controlled trials, Circadian rhythms

Published Open-Access

yes

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