BMAL1–HIF2A heterodimer modulates circadian variations of myocardial injury
Acute myocardial infarction is a leading cause of morbidity and mortality worldwide<sup>1</sup>. 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 events<sup>2-7</sup>. However, the molecular mechanisms underlying these diurnal variations remain unclear. Here we show that the core circadian transcription factor BMAL1<sup>7-11</sup> regulates circadian-dependent myocardial injury by forming a transcriptionally active heterodimer with a non-canonical partner-hypoxia-inducible factor 2 alpha (HIF2A)<sup>12-16</sup>-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)<sup>16,17</sup> 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.
Authors
- Jagat Narula (ORCID: https://orcid.org/0000-0002-0280-3996)
- Holger K. Eltzschig (ORCID: https://orcid.org/0000-0002-5676-6473)
- Joshua Gorham (ORCID: https://orcid.org/0000-0001-5969-4690)
- Xiaoyi Yuan (ORCID: https://orcid.org/0000-0002-2898-6495)
- Christine E. Seidman (ORCID: https://orcid.org/0000-0001-6380-1209)
- Zhongming Zhao (ORCID: https://orcid.org/0000-0002-3477-0914)
- Yafen Liang (ORCID: https://orcid.org/0000-0001-7902-7836)
- Matthew DeBerge (ORCID: https://orcid.org/0000-0002-9786-0327)
- Katherine Figarella (ORCID: https://orcid.org/0000-0003-3305-9167)
- Boyun Kim (ORCID: https://orcid.org/0000-0002-4973-6647)
- Dongze Zhang (ORCID: https://orcid.org/0000-0002-5510-5972)
- Jonathan G. Seidman (ORCID: https://orcid.org/0000-0002-9082-3566)
- Sary F. Aranki (ORCID: https://orcid.org/0000-0002-3129-3403)
- Xinxin Ma (ORCID: https://orcid.org/0000-0002-9942-9872)
- Kuang‐Lei Tsai (ORCID: https://orcid.org/0000-0002-5428-4219)
- Wankun Deng (ORCID: https://orcid.org/0000-0002-5052-9151)
- Seung‐Hee Yoo (ORCID: https://orcid.org/0000-0002-9930-560X)
- Jochen D. Muehlschlegel (ORCID: https://orcid.org/0000-0002-6209-7253)
- Yin‐Ying Wang
- In Hyuk Bang (ORCID: https://orcid.org/0000-0003-4666-7655)
- Wei Ruan (ORCID: https://orcid.org/0000-0002-2718-7923)
- Yu An (ORCID: https://orcid.org/0000-0002-9678-3382)
- Alemayehu A. Gorfe (ORCID: https://orcid.org/0000-0002-9328-4692)
- Fang Du (ORCID: https://orcid.org/0000-0001-8232-6693)
- Jae W. Lee (ORCID: https://orcid.org/0000-0001-5731-3831)
- Lei Li (ORCID: https://orcid.org/0000-0003-3924-2544)
- Tao Li (ORCID: https://orcid.org/0000-0003-3672-6906)
- Zhen Zhou (ORCID: https://orcid.org/0000-0002-0552-823X)
- Yanyu Wang (ORCID: https://orcid.org/0000-0001-5731-3225)
- Jiwen Li (ORCID: https://orcid.org/0000-0002-8595-860X)
- Cong Luo (ORCID: https://orcid.org/0000-0002-5159-8343)
- Ragini Nair
Institutions
- Brigham and Women's Hospital (US)
- Memorial Hermann (US)
- The University of Texas MD Anderson Cancer Center (US)
- Harvard University (US)
- Central South University (CN)
- Johns Hopkins University (US)
- Sun Yat-sen University (CN)
- Fudan University (CN)
- Johns Hopkins Medicine (US)
- Sir Run Run Shaw Hospital (CN)
- Yale University (US)
- Shenzhen Bay Laboratory (CN)
- Zhongshan Hospital (CN)
- The First Affiliated Hospital, Sun Yat-sen University (CN)
- Second Xiangya Hospital of Central South University (CN)
- The University of Texas Health Science Center (US)
- Zhejiang University (CN)
- Pukyong National University (KR)
- The University of Texas Health Science Center at Houston (US)
Publication Details
- Journal
- Nature
- Published
- 2025-04-23
- DOI
- https://doi.org/10.1038/s41586-025-08898-z
- Citations
- 35
- Primary Topic
- Circadian rhythm and melatonin
- Type
- article
- Field-Weighted Citation Impact
- 31.10