信号体调节的血清反应因子酸化 确定肌细胞的宽度与长度作为心力衰竭的治疗目标
Jinliang Li1,2, Yuliang Tan3, Catherine L Passariello2
1Departments of Ophthalmology and Medicine, Stanford Cardiovascular Institute, Stanford University, Palo Alto, CA (J.L., Xueyi Li, Y. L., Q.Y., H.T., M.S.K.).
Circulation
|September 16, 2020
概括
科学家发现了一种控制心肌细胞生长的分子开关, 这一发现为治疗病态心脏缩提供了新的治疗点.
科学领域:
- 心血管生物学
- 分子心脏病学
- 表观遗传学
背景情况:
- 与压力和体积过载相关的集中和偏心心脏缩会增加心力衰竭的风险.
- 这些缩类型涉及不对称的心肌细胞生长 (宽度与长度).
- 控制这种不对称增长的机制尚不清楚,阻碍了治疗的发展.
研究的目的:
- 阐明控制病态心肌细胞缩的分子机制.
- 确定预防或治疗心力衰竭的潜在治疗点.
主要方法:
- 使用初级成年大鼠心室肌细胞,小鼠腺相关病毒 (AAV) 介导的基因输送和人类组织样本.
- 使用染色体免疫沉与测序和精确核运行测序来定义转录调节.
- 研究了SRF酸化和相关信号通路的作用.
主要成果:
- 鉴定了SRF (血清反应因子) 酸化作为肌细胞宽度与长度增长的关键调节者,作为表观基因学开关.
- 发现由mAKAPβ组织的RSK3和PP2A双向调节SRF化.
- 在临床前模型中,通过AAV介导的基因疗法抑制RSK3或PP2A信号可以防止不良的心脏重塑并改善功能.
- 在人体扩张的心脏中观察到SRF酸化的降低,这表明治疗潜力.
结论:
- 一种涉及mAKAPβ调节的SRF酸化的新型分子开关控制心肌细胞形态变化,以应对病理性压力.
- 针对这种途径的基于AAV的基因疗法是治疗心力衰竭的有希望的转化策略.
相关概念视频
01:29Heart Failure II: Pathophysiology
512
Systolic Heart Failure and Compensatory MechanismsSystolic heart failure (also termed HFrEF, Heart Failure with Reduced Ejection Fraction) is the most prevalent type of heart filure. It results in a decreased volume of blood being pumped from the ventricle. The aortic arch and carotid sinuses have baroreceptors that detect reduced blood pressure, triggering the sympathetic nervous system (SNS) to release epinephrine and norepinephrine. Initially, this response aims to boost heart rate and...
512
01:27Transducer Mechanism: Enzyme-Linked Receptors
3.6K
Enzyme-linked receptors are cell-surface receptors acting as an enzyme or associating with an enzyme intracellularly. They make excellent drug targets. Drugs can bind to the extracellular ligand-binding domain or directly affect their enzymatic domain and alter their activity.
Major types that are helpful drug targets include:
Major types that are helpful drug targets include:
3.6K