{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"omics_type":["Unknown"],"submitter":["Ruan W"],"funding":["NIDDK NIH HHS","NHLBI NIH HHS","NIGMS NIH HHS"],"pubmed_abstract":["Acute myocardial infarction stands as a prominent cause of morbidity and mortality worldwide<sup>1-6</sup>. 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<sup>7-14</sup>. However, the molecular mechanisms that govern circadian variations of myocardial injury remain unclear. Here, we show that BMAL1<sup>14-20</sup>, 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)<sup>6,21-23</sup>, 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."],"journal":["Research square"],"pagination":["rs.3.rs-3938716"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC10925443"],"repository":["biostudies-literature"],"pubmed_title":["The BMAL1/HIF2A heterodimer modulates circadian variations of myocardial injury."],"pmcid":["PMC10925443"],"funding_grant_id":["T32 GM135118","R01 HL155950","R01 HL154720","R01 HL118266","R01 GM144836","R01 HL150401","R01 DK122796","R01 GM143587","R01 HL169519","R01 HL165748"],"pubmed_authors":["Muehlschlegel JD","Kim B","Zhang D","Liang Y","Lee J","Ma X","Ruan W","Nair R","Zhao Z","Tsai KL","Seidman CE","Eltzschig HK","Yuan X","Wang Y","Deng W","Gorham J","Li J","Abebe AG","Li L","Deberge M","Zhou Z","Yoo SH","Seidman JG","Li T","Narula J","Bang IH","Wang YY","Aranki SF","An YA"],"additional_accession":[]},"is_claimable":false,"name":"The BMAL1/HIF2A heterodimer modulates circadian variations of myocardial injury.","description":"Acute myocardial infarction stands as a prominent cause of morbidity and mortality worldwide<sup>1-6</sup>. 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<sup>7-14</sup>. However, the molecular mechanisms that govern circadian variations of myocardial injury remain unclear. Here, we show that BMAL1<sup>14-20</sup>, 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)<sup>6,21-23</sup>, 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.","dates":{"release":"2024-01-01T00:00:00Z","publication":"2024 Feb","modification":"2025-04-19T22:03:42.929Z","creation":"2025-04-19T22:03:42.929Z"},"accession":"S-EPMC10925443","cross_references":{"pubmed":["38464103"],"doi":["10.21203/rs.3.rs-3938716/v1"]}}