Notch1 Mutation Leads to Valvular Calcification Through Enhanced Myofibroblast Mechanotransduction.
Notch1 Mutation Leads to Valvular Calcification Through Enhanced Myofibroblast Mechanotransduction.
复制标题
Notch1 突变通过增强肌成纤维细胞机械传导导致瓣膜钙化。
DOI：
10.1161/atvbaha.114.305095
复制
发表时间：
2015-07
期刊：
影响因子：
--
通讯作者：
Merryman WD
中科院分区：
文献类型：
--
作者：
Chen J;Ryzhova LM;Sewell-Loftin MK;Brown CB;Huppert SS;Baldwin HS;Merryman WD
Calcific aortic valve disease (CAVD) is a significant cardiovascular disorder, and controversy exists as to whether it is primarily a dystrophic or osteogenic process in vivo. In this study, we sought to clarify the mechanism of CAVD by assessing a genetic mutation, Notch1 heterozygosity, which leads to CAVD with 100% penetrance in humans. Murine immortalized Notch1+/− aortic valve interstitial cells (AVICs) were isolated and expanded in vitro. Molecular signaling of wild type (WT) and Notch1+/− AVICs were compared to identify changes in pathways that have been linked to CAVD – TGFβ/BMP, MAPK and PI3K/Akt – and assessed for calcification potential. Additionally, AVIC mechanobiology was studied in a physiologically relevant, dynamic mechanical environment (10% cyclic strain) to investigate differences in responses between the cell types. We found that Notch1+/− AVICs resembled a myofibroblast-like phenotype expressing higher amounts of cadherin-11, a known mediator of dystrophic calcification, and decreased Runx2, a known osteogenic marker. We determined that cadherin-11 expression is regulated by Akt activity, and inhibition of Akt phosphorylation significantly reduced cadherin-11 expression. Moreover, in the presence of cyclic strain, Notch1+/− AVICs exhibited significantly upregulated phosphorylation of Akt at Ser473 and smooth muscle α-actin (αSMA) expression, indicative of a fully activated myofibroblast. Finally, these Notch1 mediated alterations led to enhanced dystrophic calcific nodule formation. This study presents novel insights in our understanding of Notch1-mediated CAVD by demonstrating that the mutation leads to AVICs that are fully activated myofibroblasts, resulting in dystrophic, but not osteogenic, calcification.
