BMAL1-HIF2A heterodimer modulates circadian variations of myocardial injury.

1. Nature. 2025 May;641(8064):1017-1028. doi: 10.1038/s41586-025-08898-z. Epub 2025 Apr 23. BMAL1-HIF2A heterodimer modulates circadian variations of myocardial injury. Ruan W(#)(1)(2), Li T(#)(3), Bang IH(#)(4), Lee J(#)(5), Deng W(6), Ma X(4), Luo C(4)(7), Du F(4)(8), Yoo SH(3), Kim B(4)(9), Li J(4)(10), Yuan X(4), Figarella K(4), An YA(4), Wang YY(6), Liang Y(4)(11), DeBerge M(4), Zhang D(4), Zhou Z(12), Wang Y(4), Gorham JM(13), Seidman JG(13), Seidman CE(13), Aranki SF(14), Nair R(4), Li L(15), Narula J(16), Zhao Z(6), Gorfe AA(17), Muehlschlegel JD(18), Tsai KL(19)(20), Eltzschig HK(21)(22). Author information: (1)Department 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. (2)Department of Anesthesiology, Second Xiangya Hospital, Central South University, Changsha, China. Wei.Ruan@uth.tmc.edu. (3)Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, McGovern Medical School, Houston, TX, USA. (4)Department of Anesthesiology, Critical Care and Pain Medicine, The University of Texas Health Science Center at Houston, McGovern Medical School, Houston, TX, USA. (5)Department of Anesthesiology, Yale University School of Medicine, New Haven, CT, USA. (6)Center for Precision Health, McWilliams School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, TX, USA. (7)Department of Anesthesiology, Second Xiangya Hospital, Central South University, Changsha, China. (8)Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, China. (9)Major in Aquaculture and Applied Life Sciences, College of Fisheries Science, Pukyong National University, Busan, Republic of Korea. (10)Department of Cardiac Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China. (11)Center for Outcomes Research, UTHealth Houston, Houston, TX, USA. (12)Division of Medical Genetics, Department of Internal Medicine, The University of Texas Health Science Center at Houston, McGovern Medical School, Houston, TX, USA. (13)Department of Genetics, Harvard Medical School, Boston, MA, USA. (14)Department of Surgery, Division of Cardiac Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. (15)Institute of Systems and Physical Biology, Shenzhen Bay Laboratory, Shenzhen, China. (16)Division of Cardiology, Department of Medicine, The University of Texas Health Science Center at Houston, McGovern Medical School, Memorial Hermann Hospital, Houston, TX, USA. (17)Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, McGovern Medical School, Houston, TX, USA. (18)Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (19)Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, McGovern Medical School, Houston, TX, USA. kuang-lei.tsai@uth.tmc.edu. (20)MD Anderson Cancer Center, UTHealth Houston Graduate School of Biomedical Sciences, Houston, TX, USA. kuang-lei.tsai@uth.tmc.edu. (21)Department of Anesthesiology, Critical Care and Pain Medicine, The University of Texas Health Science Center at Houston, McGovern Medical School, Houston, TX, USA. holger.eltzschig@uth.tmc.edu. (22)Center for Outcomes Research, UTHealth Houston, Houston, TX, USA. holger.eltzschig@uth.tmc.edu. (#)Contributed equally Update of Res Sq. 2024 Feb 28:rs.3.rs-3938716. doi: 10.21203/rs.3.rs-3938716/v1. 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 path