Ruan Wei, Li Tao, Lee Jaewoong, Bang In Hyuk, Deng Wankun, Ma Xinxin, Yoo Seung-Hee, Kim Boyun, Li Jiwen, Yuan Xiaoyi, An Yu A, Wang Yin-Ying, Liang Yafen, Deberge Matthew, Zhang Dongze, Zhou Zhen, Wang Yanyu, Gorham Josh, Seidman Jonathan G, Seidman Christine E, Aranki Sary F, Nair Ragini, Li Lei, Narula Jagat, Zhao Zhongming, Abebe Alemayehu G, Muehlschlegel Jochen Daniel, Tsai Kuang-Lei, Eltzschig Holger K
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.
Res Sq. 2024 Feb 28:rs.3.rs-3938716. doi: 10.21203/rs.3.rs-3938716/v1.
Acute myocardial infarction stands as a prominent cause of morbidity and mortality worldwide. 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. However, the molecular mechanisms that govern circadian variations of myocardial injury remain unclear. Here, we show that BMAL1, 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), 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.
急性心肌梗死是全球发病和死亡的主要原因。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，晨起发生心肌梗死的患者梗死面积更大，预后更差。然而，调控心肌损伤昼夜变化的分子机制仍不清楚。在此，我们表明核心昼夜节律转录因子BMAL1协调心肌损伤的昼夜变化。出乎意料的是，BMAL1通过与非典型伴侣缺氧诱导因子2α（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脏损伤。为证实这一发现，我们确定了BMAL1/HIF2A/DNA复合物的冷冻电镜结构，揭示了BMAL1内先前未知的结构重排能力，这使得昼夜节律与缺氧信号之间能够相互作用。此外，我们确定双调蛋白（AREG）是BMAL1/HIF2A异二聚体的节律性转录靶点，对调节心肌损伤的昼夜变化至关重要。最后，对BMAL1/HIF2A-AREG途径进行药理学靶向提供了有效的心脏保护作用，与该途径的昼夜低谷对齐时效果最佳。我们的研究结果不仅揭示了一种调控心肌损伤昼夜变化的新机制，还为基于昼夜节律的创新治疗策略铺平了道路，可能会改变目前心肌梗死的治疗模式。
