基化酶3A与SERCA2结合的破坏 增加SERCA2活动并降低慢性心力衰竭小鼠的死亡率
Jonas Skogestad1, Ingrid Albert1, Karina Hougen1
1Institute for Experimental Medical Research (J.S., I.A., K.H., M.L., O.S.E., I.V., M.B., S.M., X.S., W.E.L., P.K.L., I.S., C.R.C., J.M.A.), Oslo University Hospital and University of Oslo, Norway.
Circulation
|March 6, 2023
概括
干扰二酶3A (PDE3A) 和/内质网膜Ca2+ ATPase 2 (SERCA2) 之间的相互作用,改善了小鼠的心脏功能和生存率. 这一战略为开发用于治疗心力衰竭的SERCA2激活剂提供了一种新方法.
科学领域:
- 心血管生物学 心血管生物学
- 分子心脏病学分子心脏病学
- 药物发现 药物发现 药物发现
背景情况:
- 增加体/内等质网膜的Ca2+ ATPase 2 (SERCA2) 活性是慢性心力衰竭的治疗点.
- 目前没有选择性SERCA2激活药物.
- 二酶3A (PDE3A) 可能通过与SERCA2相互作用来限制其活性.
研究的目的:
- 为了研究SERCA2和PDE3A之间的相互作用.
- 开发可以破坏这种相互作用并激活SERCA2.2的.
- 在心力衰竭的临床前模型中评估SERCA2 / PDE3A干扰的治疗潜力.
主要方法:
- 利用先进的显微镜 (共聚焦,双色直接静态光学重建显微镜) 和生化分析 (近距离结合分析,免疫沉,基阵列,表面等离子体共振) 来研究SERCA2和PDE3A.
- 绘制了SERCA2和PDE3A之间的相互作用部位.
- 开发和优化破坏性.
- 在心肌细胞和HEK293囊泡中评估了功能影响.
- 在心力衰竭的小鼠模型中通过rAAV9输送的破坏性 (OptF) 的体内疗效和安全性进行了评估 (大动脉带).
主要成果:
- 在人类和动物心肌中,PDE3A直接与SERCA2结合 (PDE3A的氨基酸277-402到SERCA2的169-216).
- 质对PDE3A-SERCA2相互作用的干扰增加了心肌细胞中的SERCA2活性.
- 治疗rAAV9-OptF显著降低了心脏病死亡率74%,与对照组相比72%在大动脉带纹后20周.
- OptF治疗改善了心脏收缩性,没有对心脏重塑产生不良影响.
结论:
- PDE3A直接调节SERCA2活动,独立于PDE3A的催化功能.
- 针对SERCA2 / PDE3A与破坏性的相互作用,在临床前心力衰竭模型中有效预防心脏死亡率.
- 这种方法代表了开发用于治疗心力衰竭的新型SERCA2激活剂的有希望的策略.
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