BRG1 is a biomarker of hypertrophic cardiomyopathy in human heart specimens.
BRG1 is a biomarker of hypertrophic cardiomyopathy in human heart specimens.
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DOI：
10.1038/s41598-022-11829-x
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发表时间：
2022-05-17
影响因子：
4.6
通讯作者：
中科院分区：
文献类型：
--
作者：
肥厚性心肌病(HCM)是一种遗传性肌节疾病，可导致不明原因的心肌肥大，并与猝死有关。虽然之前的研究表明表观遗传修饰物BRG1在小鼠HCM模型中的作用，但还需要进一步的工作来确定它在人类中的作用。我们验证了BRG1的表达在胎儿生长发育期间心脏重塑和肥厚性心肌病发展过程中增加的假说。我们用免疫组织化学方法检测了796例人类心脏标本(81例来自肥厚型心肌病患者)中BRG1的蛋白表达，并描述了BRG1在发育早期的人胎儿心脏中的高表达。此外，我们不仅证明了BRG1在肥厚性心肌病中的表达增加，而且我们还证明了导致心力衰竭的其他疾病的BRG1表达与健康对照组相似。在人诱导的多能干细胞来源的心肌细胞中抑制BRG1显著减少MYH7，增加MYH6，提示BRG1在人肥厚性心肌中两种肌球蛋白重链亚型的病理失衡中起调节作用。这些数据首次证明BRG1是人类HCM的特异性生物标志物，并为未来人类心脏病的表观遗传学研究奠定了基础。
Hypertrophic cardiomyopathy (HCM) is a genetic disease of the sarcomere that causes otherwise unexplained cardiac hypertrophy and is associated with sudden death. While previous studies showed the role of the epigenetic modifier Brg1 in mouse models of HCM, additional work is needed to identify its role in humans. We tested the hypothesis that BRG1 expression is increased in periods of cardiac remodeling during fetal growth and in development of HCM. We employed immunohistochemical staining to evaluate protein expression of BRG1 in 796 human cardiac specimens (81 from patients with HCM) and describe elevated BRG1 expression in human fetal hearts in early development. In addition, we not only demonstrate increased expression of BRG1 in HCM, but we also show that other diseases that lead to heart failure have similar BRG1 expression to healthy controls. Inhibition of BRG1 in human induced pluripotent stem cell-derived cardiomyocytes significantly decreases MYH7 and increases MYH6, suggesting a regulatory role for BRG1 in the pathological imbalance of the two myosin heavy chain isoforms in human HCM. These data are the first demonstration of BRG1 as a specific biomarker for human HCM and provide foundation for future studies of epigenetics in human cardiac disease.
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Marian AJ
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通讯作者：
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