The BMAL1/HIF2A heterodimer modulates circadian variations of myocardial injury.

Autor:	Ruan W; Department of Anesthesiology, Critical Care and Pain Medicine, The University of Texas Health Science Center at Houston, McGovern Medical School, Houston, TX, 77030, USA.; Department of Anesthesiology, Second Xiangya Hospital, Central South University, Changsha, 410011, China.; These authors contributed equally., Li T; Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, McGovern Medical School, Houston, TX, 77030, USA.; These authors contributed equally., Lee J; Department of Anesthesiology, Yale University School of Medicine, New Haven, CT, 06510, USA.; These authors contributed equally., Bang IH; Department of Anesthesiology, Critical Care and Pain Medicine, The University of Texas Health Science Center at Houston, McGovern Medical School, Houston, TX, 77030, USA., Deng W; Center for Precision Health, McWilliams School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA., Ma X; Department of Anesthesiology, Critical Care and Pain Medicine, The University of Texas Health Science Center at Houston, McGovern Medical School, Houston, TX, 77030, USA., Yoo SH; Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, McGovern Medical School, Houston, TX, 77030, USA., Kim B; Department of Anesthesiology, Critical Care and Pain Medicine, The University of Texas Health Science Center at Houston, McGovern Medical School, Houston, TX, 77030, USA., Li J; Department of Anesthesiology, Critical Care and Pain Medicine, The University of Texas Health Science Center at Houston, McGovern Medical School, Houston, TX, 77030, USA.; Department of Cardiac Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, China., Yuan X; Department of Anesthesiology, Critical Care and Pain Medicine, The University of Texas Health Science Center at Houston, McGovern Medical School, Houston, TX, 77030, USA., An YA; Department of Anesthesiology, Critical Care and Pain Medicine, The University of Texas Health Science Center at Houston, McGovern Medical School, Houston, TX, 77030, USA., Wang YY; Center for Precision Health, McWilliams School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA., Liang Y; Department of Anesthesiology, Critical Care and Pain Medicine, The University of Texas Health Science Center at Houston, McGovern Medical School, Houston, TX, 77030, USA., Deberge M; Department of Anesthesiology, Critical Care and Pain Medicine, The University of Texas Health Science Center at Houston, McGovern Medical School, Houston, TX, 77030, USA., Zhang D; Department of Anesthesiology, Critical Care and Pain Medicine, The University of Texas Health Science Center at Houston, McGovern Medical School, Houston, TX, 77030, USA., Zhou Z; Division of Medical Genetics, Department of Internal Medicine, The University of Texas Health Science Center at Houston, McGovern Medical School, Houston, TX, 77030, USA., Wang Y; Department of Anesthesiology, Critical Care and Pain Medicine, The University of Texas Health Science Center at Houston, McGovern Medical School, Houston, TX, 77030, USA., Gorham J; Department of Genetics, Harvard Medical School, Boston, MA, 02115, USA., Seidman JG; Department of Genetics, Harvard Medical School, Boston, MA, 02115, USA., Seidman CE; Department of Genetics, Harvard Medical School, Boston, MA, 02115, USA., Aranki SF; Department of Surgery, Division of Cardiac Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA., Nair R; Department of Anesthesiology, Critical Care and Pain Medicine, The University of Texas Health Science Center at Houston, McGovern Medical School, Houston, TX, 77030, USA., Li L; Institute of Systems and Physical Biology, Shenzhen Bay Laboratory, Shenzhen, 518055, China., Narula J; Weatherhead PET Center for Preventing and Reversing Atherosclerosis, Division of Cardiology, Department of Medicine, The University of Texas Health Science Center at Houston, McGovern Medical School, Memorial Hermann Hospital, Houston, TX, 77030, USA., Zhao Z; Center for Precision Health, McWilliams School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA., Abebe AG; Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, McGovern Medical School, Houston, TX, 77030, USA., Muehlschlegel JD; Department of Anesthesiology and Critical Care Medicine, Johns Hopkins Medicine, Baltimore, MD, 21287, USA., Tsai KL; Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, McGovern Medical School, Houston, TX, 77030, USA.; MD Anderson Cancer Center, UTHealth Houston Graduate School of Biomedical Sciences, Houston, TX, USA., Eltzschig HK; Department of Anesthesiology, Critical Care and Pain Medicine, The University of Texas Health Science Center at Houston, McGovern Medical School, Houston, TX, 77030, USA.; Outcomes Research Consortium, Cleveland, OH, USA.
Jazyk:	angličtina
Zdroj:	Research square [Res Sq] 2024 Feb 28. Date of Electronic Publication: 2024 Feb 28.
DOI:	10.21203/rs.3.rs-3938716/v1
Abstrakt:	Acute myocardial infarction stands as a prominent cause of morbidity and mortality worldwide 1-6 . 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 infarctions 7-14 . However, the molecular mechanisms that govern circadian variations of myocardial injury remain unclear. Here, we show that BMAL1 14-20 , 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. Competing Interests: Competing interests The authors declare no competing interests.
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu