位于休斯顿的德克萨斯大学Holger K. Eltzschig课题组在研究中取得进展。他们报道了BMAL1-HIF2A异源二聚体调节心肌损伤的昼夜变化。相关论文于2025年4月23日发表在《自然》杂志上。

本研究表明，核心昼夜节律转录因子BMAL1通过与非规范伴侣-缺氧诱导因子2 α (HIF2A)形成转录活性异二聚体，以昼夜方式调节昼夜节律依赖性心肌损伤。为了证实这一发现，小组确定了BMAL1–HIF2A–DNA复合体的低温电镜结构，揭示了BMAL1内部的结构重排，使昼夜节律和缺氧信号之间产生串扰。BMAL1通过增强HIF2A的转录活性和稳定HIF2A蛋白来调节昼夜缺氧反应。该研究团队进一步确定了双调节蛋白（AREG）作为BMAL1-HIF2A复合体的节律靶点，对调节心肌损伤的日间变化至关重要。在药理学上靶向BMAL1-HIF2A-AREG通路提供心脏保护，当与该通路的昼夜节律相一致时，其效果最大。这些发现确定了控制心肌损伤昼夜变化的机制，并强调了基于时钟的药物干预治疗缺血性心脏病的治疗潜力。

据悉，急性心肌梗死是世界范围内发病率和死亡率的主要原因。临床研究表明，心肌梗死后心脏损伤的严重程度呈现昼夜节律模式，发生晨起事件的患者梗死面积较大，预后较差。然而，这些昼夜变化背后的分子机制仍不清楚。

附：英文原文

Title: BMAL1–HIF2A heterodimer modulates circadian variations of myocardial injury

Author: Ruan, Wei, Li, Tao, Bang, In Hyuk, Lee, Jaewoong, Deng, Wankun, Ma, Xinxin, Luo, Cong, Du, Fang, Yoo, Seung-Hee, Kim, Boyun, Li, Jiwen, Yuan, Xiaoyi, Figarella, Katherine, An, Yu A., Wang, Yin-Ying, Liang, Yafen, DeBerge, Matthew, Zhang, Dongze, Zhou, Zhen, Wang, Yanyu, Gorham, Joshua M., Seidman, Jonathan G., Seidman, Christine E., Aranki, Sary F., Nair, Ragini, Li, Lei, Narula, Jagat, Zhao, Zhongming, Gorfe, Alemayehu A., Muehlschlegel, Jochen D., Tsai, Kuang-Lei, Eltzschig, Holger K.

Issue&Volume: 2025-04-23

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 events2,3,4,5,6,7. However, the molecular mechanisms underlying these diurnal variations remain unclear. Here we show that the core circadian transcription factor BMAL17,8,9,10,11 regulates circadian-dependent myocardial injury by forming a transcriptionally active heterodimer with a non-canonical partner—hypoxia-inducible factor 2 alpha (HIF2A)12,13,14,15,16—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.

DOI: 10.1038/s41586-025-08898-z

Source: https://www.nature.com/articles/s41586-025-08898-z