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血管光滑肌肉细胞表型切换和PRMT5的neointimal形成的表观遗传调节

Ni Zhu¹, Zhi-Fu Guo¹, Kyosuke Kazama¹

¹Center for Translational Medicine, Department of Medicine, Thomas Jefferson University, 1020 Locust St, Philadelphia, PA 19107, USA.

Cardiovascular research

|July 24, 2023

概括

蛋白质氨酸甲基转移酶5 (PRMT5) 驱动血管光滑肌细胞 (VSMC) 过渡和血管重塑. 抑制PRMT5为扩散性血管疾病提供了潜在的治疗策略.

科学领域:

血管生物学血管生物学
表观遗传学在表观遗传学中,表观遗传学是指表观遗传学.
心血管疾病心血管疾病

背景情况:

血管光滑肌细胞 (VSMC) 现型切换是诸如动脉样硬化和高血压等心血管疾病的核心.
蛋白质氨酸甲基转移酶 (PRMTs) 在VSMC生物学和血管重塑中的作用尚不清楚.

研究的目的:

调查PRMT在VSMC表型转换中的作用.
确定PRMTs在受伤后血管重塑中的功能.

主要方法:

在人类大动脉SMC,PDGF刺激的VSMC,动脉样硬化病变和受伤的老鼠动脉中使用西斑和免疫组织化学评估PRMT5的表达.
操纵PRMT5表达 (过度表达和沉默) 以研究其对VSMC扩散和迁移的影响.
研究了涉及基因组甲基化和乙化的表观遗传机制.
使用小鼠模型与SMC特定的PRMT5删除和老鼠动脉损伤模型与lentiviral shPRMT5输送.
在小鼠动脉绑定模型中使用PRMT5抑制剂EPZ015666.

主要成果:

在VSMC中PRMT5的表达很高,在疾病状态和血管损伤后上调.
PRMT5的过度表达促进了VSMC的增殖和迁移,同时抑制了SMC标记基因表达.
PRMT5通过调节基因组甲基化 (H3R8,H4R3) 和影响乙化 (H3K9,H4) 来影响VSMC表型,从而影响SRF/肌肉激素复合物的结合.
在动物模型中,基因删除和药理上抑制PRMT5都显著减少了血管损伤后的neointimal形成.

结论:

PRMT5被确定为VSMC表型切换的新型调节者.
向PRMT5为治疗多发性血管疾病提供了一个有希望的治疗途径.

关键词:

基因组合物基因组合物甲基化甲基化甲基化在PRMT5中,现象类型的开关核武器的扩散顺滑肌肉细胞是一种平滑肌肉细胞.

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