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恢复受损的内皮肌细胞增强因子2功能挽救了肺动脉高血压

Jongmin Kim¹, Cheol Hwangbo¹, Xiaoyue Hu¹

¹From the Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Yale University School of Medicine, New Haven, CT (J.K., C.H., X.H., Y.K., I.P., D.M., H.P., H.J., D.L.M., H.J.C.); the Department of Life Systems, Sookmyung Women's University, Seoul, Korea (J.K.); and the Department of Pathobiology, The Lerner Institute, The Cleveland Clinic Foundation, Cleveland, OH (S.A.C., S.C.E.).

|October 23, 2014

概括

肺动脉高血压 (PAH) 涉及细胞中肌细胞增强因子2 (MEF2) 活性受损. 抑制特定的基因组脱乙酶 (HDACs) 恢复了MEF2功能,并改善了PAH模型.

科学领域:

心血管研究研究心血管研究
分子生物学分子生物学
细胞病理生理学

背景情况:

肺动脉高血压 (PAH) 是一种严重的疾病,其特征是肺动脉的高血压和右心力衰竭.
肺血管中的异常细胞增殖有助于PAH的发病.
了解肺血管平衡中的转录调节是开发新疗法的关键.

研究的目的:

研究转录因子肌细胞增强因子2 (MEF2) 在肺动脉高血压 (PAH) 中的作用.
确定PAH中受损MEF2活性背后的机制.
评估针对PAH中MEF2活性的治疗潜力.

主要方法:

从PAH患者的肺动脉内皮细胞 (PAEC) 中评估了MEF2活性.
确定了参与血管平衡的MEF2调节基因.
研究了IIa类组素脱乙酶 (HDAC4和HDAC5) 在MEF2抑制中的作用.
在PAH的细胞和动物模型中使用了选择性IIa类HDAC抑制剂.

主要成果:

在PAH患者的PAEC中,MEF2活性显著降低.
关键的MEF2向基因,包括微RNA和克鲁佩尔类似因子,在PAHPAEC中被下调.
过多的HDAC4和HDAC5核积累导致MEF2活动的受损.
对IIa类HDACs的药理抑制恢复了MEF2活性,减少了细胞增殖,并改善了PAH实验模型.

结论:

增加MEF2活性为PAH提供了一个有前途的治疗策略.
选择性抑制IIa类HDACs为PAH治疗提供了有针对性的方法,有可能避免广泛的HDAC抑制的副作用.

关键词:

它们是内皮细胞的内皮细胞.肺高血压是一种肺高血压.转录激活的转录激活

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