Cadherin-11 regulates cell-cell tension necessary for calcific nodule formation by valvular myofibroblasts.
Cadherin-11 regulates cell-cell tension necessary for calcific nodule formation by valvular myofibroblasts.
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DOI：
10.1161/atvbaha.112.300278
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发表时间：
2013-01
期刊：
影响因子：
--
通讯作者：
Merryman WD
中科院分区：
文献类型：
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作者：
Hutcheson JD;Chen J;Sewell-Loftin MK;Ryzhova LM;Fisher CI;Su YR;Merryman WD
Dystrophic calcific nodule formation in vitro involves differentiation of aortic valve interstitial cells (AVICs) into a myofibroblast phenotype. Interestingly, inhibition of the kinase MEK1/2 prevents calcific nodule formation despite leading to myofibroblast activation of AVICs, indicating the presence of an additional mechanotransductive component required for calcific nodule morphogenesis. In this study, we assess the role of TGF-β1-induced cadherin-11 expression in calcific nodule formation. As shown previously, porcine AVICs treated with TGF-β1 prior to cyclic strain exhibit increased myofibroblast activation and significant calcific nodule formation. In addition to an increase in contractile myofibroblast markers, TGF-β1 treated AVICs exhibit significantly increased expression of cadherin-11. This expression is inhibited by the addition of U0126, a specific MEK1/2 inhibitor. The role of increased cadherin-11 is revealed through a wound assay, which demonstrates increased intercellular tension in TGF-β1 treated AVICs possessing cadherin-11. Furthermore, when siRNA is used to knockdown cadherin-11, calcific nodule formation is abrogated, indicating that robust cell-cell connections are necessary in generating tension for calcific nodule morphogenesis. Finally, we demonstrate enrichment of cadherin-11 in human calcified leaflets. These results indicate the necessity of cadherin-11 for dystrophic calcific nodule formation, which proceeds through an Erk1/2 dependent pathway.
