Hulin Alexia, Moore Vicky, James Jeanne M, Yutzey Katherine E
Division of Molecular Cardiovascular Biology, The Heart Institute, Cincinnati Children's Hospital Medical Center, ML7020, 240 Albert Sabin Way, Cincinnati, OH 45229, USA.
Division of Cardiology, The Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
Cardiovasc Res. 2017 Jan;113(1):40-51. doi: 10.1093/cvr/cvw229. Epub 2016 Nov 7.
Myxomatous valve disease (MVD) is the most common aetiology of primary mitral regurgitation. Recent studies suggest that defects in heart valve development can lead to heart valve disease in adults. Wnt/β-catenin signalling is active during heart valve development and has been reported in human MVD. The consequences of increased Wnt/β-catenin signalling due to Axin2 deficiency in postnatal valve remodelling and pathogenesis of MVD were determined.
To investigate the role of Wnt/β-catenin signalling, we analysed heart valves from mice deficient in Axin2 (KO), a negative regulator of Wnt/β-catenin signalling. Axin2 KO mice display enlarged mitral and aortic valves (AoV) after birth with increased Wnt/β-catenin signalling and cell proliferation, whereas Sox9 expression and collagen deposition are decreased. At 2 months in Axin2 KO mice, the valve extracellular matrix (ECM) is stratified but distal AoV leaflets remain thickened and develop aortic insufficiency. Progressive myxomatous degeneration is apparent at 4 months with extensive ECM remodelling and focal aggrecan-rich areas, along with increased BMP signalling. Infiltration of inflammatory cells is also observed in Axin2 KO AoV prior to ECM remodelling. Overall, these features are consistent with the progression of human MVD. Finally, Axin2 expression is decreased and Wnt/β-catenin signalling is increased in myxomatous mitral valves in a murine model of Marfan syndrome, supporting the importance of Wnt/β-catenin signalling in the development of MVD.
Altogether, these data indicate that Axin2 limits Wnt/β-catenin signalling after birth and allows proper heart valve maturation. Moreover, dysregulation of Wnt/β-catenin signalling resulting from loss of Axin2 leads to progressive MVD.
黏液瘤样瓣膜病（MVD）是原发性二尖瓣反流最常见的病因。最近的研究表明，心脏瓣膜发育缺陷可导致成人心脏瓣膜病。Wnt/β-连环蛋白信号通路在心脏瓣膜发育过程中活跃，且在人类MVD中也有报道。本研究旨在确定出生后瓣膜重塑过程中由于Axin2缺乏导致的Wnt/β-连环蛋白信号通路增强对MVD发病机制的影响。
为了研究Wnt/β-连环蛋白信号通路的作用，我们分析了Axin2基因敲除（KO）小鼠的心脏瓣膜，Axin2是Wnt/β-连环蛋白信号通路的负调节因子。Axin2 KO小鼠出生后二尖瓣和主动脉瓣（AoV）增大，Wnt/β-连环蛋白信号通路增强，细胞增殖增加，而Sox9表达和胶原蛋白沉积减少。在Axin2 KO小鼠2个月时，瓣膜细胞外基质（ECM）分层，但远端AoV瓣叶仍增厚并出现主动脉瓣关闭不全。4个月时出现进行性黏液瘤样变性，伴有广泛的ECM重塑和富含聚集蛋白聚糖的局灶性区域，同时BMP信号通路增强。在ECM重塑之前，Axin2 KO AoV中也观察到炎症细胞浸润。总体而言，这些特征与人类MVD的进展一致。最后，在马凡综合征小鼠模型的黏液瘤样二尖瓣中，Axin2表达降低，Wnt/β-连环蛋白信号通路增强，这支持了Wnt/β-连环蛋白信号通路在MVD发展中的重要性。
总之，这些数据表明Axin2在出生后限制Wnt/β-连环蛋白信号通路，使心脏瓣膜正常成熟。此外，Axin2缺失导致的Wnt/β-连环蛋白信号通路失调会导致进行性MVD。
