From the Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore (C.Y.T., J.X.W., P.S.C., H.T., D.L., W.C., J.J.).
Cardiovascular Research Institute, National University Health System, Centre for Translational Medicine, Singapore (C.Y.T., J.X.W., P.S.C., H.T., D.L., W.C., M.A.-J., J.W.W., R.S.F., J.J.).
Circ Res. 2019 Oct 11;125(9):834-846. doi: 10.1161/CIRCRESAHA.119.314794. Epub 2019 Sep 9.
Pathogenic variations in the lamin gene () cause familial dilated cardiomyopathy (DCM). insufficiency caused by pathogenic variants is believed to be the basic mechanism underpinning -related DCM.
To assess whether silencing of cardiac causes DCM and investigate the role of Yin Yang 1 () in suppressing DCM.
We developed a DCM mouse model induced by cardiac-specific short hairpin RNA. Silencing of cardiac induced DCM with associated cardiac fibrosis and inflammation. We demonstrated that upregulation of suppressed DCM and cardiac fibrosis by inducing expression and preventing upregulation of . Knockdown of upregulated attenuated the suppressive effect of on DCM and cardiac fibrosis. However, upregulation of alone was not sufficient to suppress DCM and cardiac fibrosis. Importantly, upregulation of together with silencing significantly suppressed DCM and cardiac fibrosis. Mechanistically, upregulation of regulated and reporter activities and modulated and gene expression in cardiomyocytes. Downregulation of inhibited TGF-β (transforming growth factor-β)/Smad signaling in DCM hearts. Regulation of both and further suppressed TGFβ/Smad signaling. In addition, co-modulation of and reduced CD3+ T cell numbers in DCM hearts.
Our findings demonstrate that upregulation of or co-modulation of and offer novel therapeutic strategies for the treatment of DCM caused by insufficiency.
层粘连蛋白基因 () 的致病变异可引起家族性扩张型心肌病 (DCM)。致病性变异导致的 不足被认为是 -相关 DCM 的基本机制。
评估心脏 沉默是否会导致 DCM，并研究阴阳 1 () 在抑制 DCM 中的作用。
我们开发了一种心脏特异性短发夹 RNA 诱导的 DCM 小鼠模型。心脏 沉默可诱导 DCM 伴心肌纤维化和炎症。我们证明上调 可通过诱导 表达和防止 上调来抑制 DCM 和心肌纤维化。下调上调可减弱 对 DCM 和心肌纤维化的抑制作用。然而，上调 本身不足以抑制 DCM 和心肌纤维化。重要的是，上调 与 沉默一起可显著抑制 DCM 和心肌纤维化。机制上，上调 调节心肌细胞中的 和 报告基因活性，并调节 和 基因表达。下调 可抑制 DCM 心脏中的 TGF-β（转化生长因子-β）/Smad 信号。 和 进一步调节 TGFβ/Smad 信号。此外， 与 的共同调节可减少 DCM 心脏中的 CD3+T 细胞数量。
我们的研究结果表明，上调 或 与 的共同调节为治疗由 不足引起的 DCM 提供了新的治疗策略。
