通过增强心脏脂肪酸代谢和线粒体功能的新型泛ERR激活剂改善心脏衰竭
Weiyi Xu1, Cyrielle Billon2,3, Hui Li1
1Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX (W.X., H.L., A.W., L.Q., A.G., J.R.D.C.R., Y.Z., K.Y., M.L., E.N., A.M., L.Z.).
Circulation
|November 14, 2023
概括
与雌激素相关的受体 (ERR) 激动剂通过增强心脏代谢和功能来改善心脏衰竭. 这些发现支持ERR激应剂作为潜在的心力衰竭新疗法.
科学领域:
- 心血管生物学
- 代谢调节
- 药理学
背景情况:
- 心脏代谢功能障碍是心力衰竭的一个关键特征.
- 与雌激素相关的受体 (ERR) 对于调节心脏代谢至关重要.
- 针对ERR提供了对HF的潜在治疗策略,但没有合适的体内化合物.
研究的目的:
- 设计和合成新的泛ERR激应剂.
- 在压力过载诱导的HF模型中评估ERR激动剂的疗效.
- 阐明HF中ERR激应的分子机制和异型依赖性.
主要方法:
- 基于结构的药物设计产生了两种不同的泛ERR激动剂 (SLU-PP-332和SLU-PP-915).
- 在体内研究评估了HF小鼠模型中的心脏功能,存活率和心脏重塑.
- 用多组,遗传依赖和体外测试来确定机制和特异性.
主要成果:
- 在小鼠中,ERR激动剂显著改善了心脏功能,减少了纤维化,并增加了存活率,但没有导致过度增长.
- 转录组和代谢组分析显示脂肪酸代谢和线粒体功能得到改善.
- 确定ERRγ是ERR激动的心脏保护作用的主要媒介.
结论:
- 治疗ERR激动剂可保护心脏氧化代谢,防止压力过重引起的HF.
- 这些发现为开发ERR激动剂作为新型HF疗法提供了药理学证据.
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