在BMAL1/HIF2A异构体调节心肌损伤的昼夜变化
Wei Ruan1,2,3, Tao Li4,3, Jaewoong Lee5,3
1Department of Anesthesiology, Critical Care and Pain Medicine, The University of Texas Health Science Center at Houston, McGovern Medical School, Houston, TX, 77030, USA.
Research square
|March 11, 2024
概括
核心昼夜因素BMAL1,与HIF2A合作,控制心脏病发作损伤的每日变化. 针对这种BMAL1/HIF2A-AREG通路提供心脏保护,最有效的时间是该通路的每日最低值.
科学领域:
- 心血管生物学 心血管生物学
- 时间生物学 时间生物学
- 分子医学是分子医学.
背景情况:
- 急性心肌梗塞是全球主要的死亡原因.
- 心肌梗塞中心脏损伤严重程度显示昼夜变化,在早晨事件中结果更差.
- 肌肉心脏损伤中这些昼夜变化背后的分子机制尚不清楚.
研究的目的:
- 阐明心肌损伤中昼夜变化背后的分子机制.
- 为了确定关键的分子参与者参与心脏损伤的日间调节.
- 探索基于昼夜节律的心肌梗塞的潜在治疗点.
主要方法:
- 研究了昼夜转录因子BMAL1在心肌损伤中的作用.
- 使用冷电子显微镜 (cryo-EM) 来确定BMAL1/HIF2A/DNA复合物的结构.
- 鉴定并验证了安菲瑞古林 (AREG) 作为BMAL1/HIF2A异构体的基因.
- 在心脏保护模型中评估了BMAL1/HIF2A-AREG途径的药理向疗效.
主要成果:
- 在心肌损伤中,BMAL1调节了白天的变化.
- BMAL1与HIF2A形成了白天异构体,将昼夜节律和缺氧信号联系起来.
- 该BMAL1/HIF2A复合体以节奏方式调节安菲瑞古林 (AREG) 表达.
- 对BMAL1/HIF2A-AREG途径的药理向证明了心脏保护,有效性取决于时间.
结论:
- BMAL1和HIF2A形成了一种新型的昼夜异构体,它控制心肌损伤的白天变化.
- 该BMAL1/HIF2A-AREG通路代表了一个新的分子机制,用于心脏损伤的昼夜调节.
- 针对这种途径提供了一个有前途的策略,用于心肌梗塞的昼夜性心脏保护.
- 定时干预BMAL1/HIF2A-AREG通路的昼夜低谷,最大限度地提高治疗效益.
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