TGF- signalling and reactive oxygen species drive fibrosis and matrix remodelling in myxomatous mitral valves
TGF- signalling and reactive oxygen species drive fibrosis and matrix remodelling in myxomatous mitral valves
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DOI：
10.1093/cvr/cvt083
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发表时间：
2013-07-01
影响因子：
10.8
通讯作者：
Miller, Jordan D.
中科院分区：
文献类型：
--
作者：
Hagler, Michael A.;Hadley, Thomas M.;Miller, Jordan D.
粘液瘤性二尖瓣疾病（MMVD）与瓣叶增厚、纤维化、基质重塑和瓣叶脱垂相关。然而，导致MMVD的分子机制仍然知之甚少。我们测试了这样的假设，即增加的转化生长因子-（TGF-β）信号传导和活性氧（ROS）是人类和小鼠二尖瓣中促纤维化基因表达的主要贡献者。我们发现，在患有MMVD的人（n 24）的二尖瓣中，TGF-1的表达增加与结缔组织生长因子（CTGF）和基质金属蛋白酶2（MMP 2）的表达增加相关。.磷酸化SMAD 2/3（蛋白质印迹法）和SMAD特异性E3泛素蛋白连接酶（SMURF）1和2（qRTPCR）表达水平的增加表明TGF-1信号传导通过经典信号传导级联发生。人MMVD组织中氧化应激（二氢乙锭染色）增加，并与NAD（P）H氧化酶催化亚基（Nox）2和4增加相关，尽管超氧化物歧化酶1（SOD 1）增加。在来自SOD 1缺陷小鼠的二尖瓣中，CTGF、MMP 2、Nox 2和Nox 4的表达显著增加，表明ROS可以独立地激活促纤维化和基质重塑基因表达模式。此外，用细胞可渗透的抗氧化剂处理小鼠二尖瓣间质细胞在体外减弱了TGF-1诱导的促纤维化和基质重塑基因表达。典型TGF-信号传导的激活是MMVD中纤维化和基质重塑的主要贡献者，并且通过氧化应激的增加而放大。旨在降低早期MMVD中TGF-β活化和氧化应激的治疗可能减缓MMVD的进展。
Myxomatous mitral valve disease (MMVD) is associated with leaflet thickening, fibrosis, matrix remodelling, and leaflet prolapse. Molecular mechanisms contributing to MMVD, however, remain poorly understood. We tested the hypothesis that increased transforming growth factor- (TGF-) signalling and reactive oxygen species (ROS) are major contributors to pro-fibrotic gene expression in human and mouse mitral valves.Using qRTPCR, we found that increased expression of TGF-1 in mitral valves from humans with MMVD (n 24) was associated with increased expression of connective tissue growth factor (CTGF) and matrix metalloproteinase 2 (MMP2). Increased levels of phospho-SMAD2/3 (western blotting) and expression of SMAD-specific E3 ubiquitin-protein ligases (SMURF) 1 and 2 (qRTPCR) suggested that TGF-1 signalling occurred through canonical signalling cascades. Oxidative stress (dihydroethidium staining) was increased in human MMVD tissue and associated with increases in NAD(P)H oxidase catalytic subunits (Nox) 2 and 4, occurring despite increases in superoxide dismutase 1 (SOD1). In mitral valves from SOD1-deficient mice, expression of CTGF, MMP2, Nox2, and Nox4 was significantly increased, suggesting that ROS can independently activate pro-fibrotic and matrix remodelling gene expression patterns. Furthermore, treatment of mouse mitral valve interstitial cells with cell permeable antioxidants attenuated TGF-1-induced pro-fibrotic and matrix remodelling gene expression in vitro.Activation of canonical TGF- signalling is a major contributor to fibrosis and matrix remodelling in MMVD, and is amplified by increases in oxidative stress. Treatments aimed at reducing TGF- activation and oxidative stress in early MMVD may slow progression of MMVD.