ERK1/2 directly acts on CTGF/CCN2 expression to mediate myocardial fibrosis in cardiomyopathy caused by mutations in the lamin A/C gene
ERK1/2 directly acts on CTGF/CCN2 expression to mediate myocardial fibrosis in cardiomyopathy caused by mutations in the lamin A/C gene
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DOI：
10.1093/hmg/ddw090
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发表时间：
2016-06-01
影响因子：
3.5
通讯作者：
Muchir, Antoine
中科院分区：
文献类型：
--
作者：
Chatzifrangkeskou, Maria;Le Dour, Caroline;Muchir, Antoine
由核纤层蛋白A/C基因突变引起的心肌病（LMNA心肌病）的特征在于心肌纤维化增加，其损害左心室舒张并易于发生心力衰竭和心脏传导异常。虽然我们以前发现LMNA心肌病心脏细胞外信号调节激酶1/2（ERK 1/2）活性异常升高，但其在心肌纤维化发展中的作用尚不清楚。我们现在发现，转化生长因子（TGF）-β/Smad信号参与LMNA心肌病中ERK 1/2信号的激活。ERK 1/2通过调节结缔组织生长因子（CTGF/CCN 2）的表达而介导心肌纤维化和左室功能不全。体内研究表明，使用特异性抗体抑制CTGF/CCN 2可减少心肌纤维化并改善左心室功能障碍。总之，这些发现表明心脏ERK 1/2活性部分受TGF-β/Smad信号转导调节，导致CTGF/CCN 2活化改变，从而介导纤维化并改变心脏功能。这确定了LMNA心肌病发展的新机制。
Cardiomyopathy caused by lamin A/C gene mutations (LMNA cardiomyopathy) is characterized by increased myocardial fibrosis, which impairs left ventricular relaxation and predisposes to heart failure, and cardiac conduction abnormalities. While we previously discovered abnormally elevated extracellular signal-regulated kinase 1/2 (ERK1/2) activities in heart in LMNA cardiomyopathy, its role on the development of myocardial fibrosis remains unclear. We now showed that transforming growth factor (TGF)-beta/Smad signaling participates in the activation of ERK1/2 signaling in LMNA cardiomyopathy. ERK1/2 acts on connective tissue growth factor (CTGF/CCN2) expression to mediate the myocardial fibrosis and left ventricular dysfunction. Studies in vivo demonstrate that inhibiting CTGF/CCN2 using a specific antibody decreases myocardial fibrosis and improves the left ventricular dysfunction. Together, these findings show that cardiac ERK1/2 activity is modulated in part by TGF-beta/Smad signaling, leading to altered activation of CTGF/CCN2 to mediate fibrosis and alter cardiac function. This identifies a novel mechanism in the development of LMNA cardiomyopathy.