Cadherin-11 as a regulator of valve myofibroblast mechanobiology
Cadherin-11 as a regulator of valve myofibroblast mechanobiology
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DOI：
10.1152/ajpheart.00277.2018
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发表时间：
2018-12-01
影响因子：
4.8
通讯作者：
Merryman, W. David
中科院分区：
文献类型：
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作者：
Bowler, Meghan A.;Bersi, Matthew R.;Merryman, W. David
Cadherin-11 (CDH11) 在多种纤维化疾病中表达上调。包括关节炎和钙化性主动脉瓣疾病。我们最近的工作已将 CDH11 确定为潜在的治疗靶点，并表明使用 CDH11 功能阻断抗体治疗可以预防小鼠钙化主动脉瓣疾病的特征。本研究调查了 CDH11 在调节被认为导致钙化的瓣膜间质细胞的机械生物学行为中的作用。主动脉瓣间质细胞从Cdh11(+/+)、Cdh11(+/-)和Cdh11(-/-)、immortomice中收获。将细胞置于炎症细胞因子、转化生长因子 (TGF)-β(1) 和 IL-6 作用下，以表征 CDH11 调节其机械生物学变化的分子机制。对 Cdh11(+/+)、Cdh11(+/-) 和 Cdh11(-)(/-) 小鼠的主动脉瓣进行组织学分析，以确定体内对 CDH11 缺失的关键反应。我们发现 CDH11 通过调节收缩性和通过粘着斑抑制底物的能力来影响细胞行为。我们还发现，转化生长因子-β(1) 会破坏 CDH11 和平滑肌 α-肌动蛋白之间的正常关系，从而加剧肌成纤维细胞疾病表型。这种表型转换通过 IL-6 信号轴得到增强，并且可以作为正反馈回路中相邻主动脉瓣间质细胞中肌成纤维细胞激活的旁分泌机制。这些数据表明 CDH11 是肌成纤维细胞表型的重要介质，并确定了它调节细胞行为的多种机制。新的和值得注意的 Cadherin-11 通过调节粘着斑和炎症细胞因子分泌来影响瓣膜间质细胞收缩性。转化生长因子-β(1) 会破坏钙粘蛋白-11 和平滑肌 α-肌动蛋白表达之间的正常平衡，从而促进肌成纤维细胞表型。 C.adherin-11 对于 IL-6 和几丁质酶 3 样蛋白 1 的分泌是必需的，并且 IL-6 促进收缩性。靶向 cadherin-11 可以在治疗上以多方面的方式影响瓣膜间质细胞表型。
Cadherin-11 (CDH11) is upregulated in a variety of fibrotic diseases. including arthritis and calcific aortic valve disease. Our recent work has identified CDH11 as a potential therapeutic target and shown that treatment with a CDH11 functional blocking antibody can prevent hallmarks of calcific aortic valve disease in mice. The present study investigated the role of CDH11 in regulating the mechanobiological behavior of valvular interstitial cells believed to cause calcification. Aortic valve interstitial cells were harvested from Cdh11(+/+), Cdh11(+/-),and Cdh11(-/-), immortomice. Cells were subjected to inflammatory cytokines transforming growth factor (TGF)-beta(1), and IL-6 to characterize the molecular mechanisms by which CDH11 regulates their mechanobiological changes. Histology was performed on aortic valves from Cdh11(+/+), Cdh11(+/-), and Cdh11(-)(/-) mice to identify key responses to CDH11 deletion in vivo. We showed that CDH11 influences cell behavior through its regulation of contractility and its ability to hind substrates via focal adhesions. We also show that transforming growth factor-beta(1) overrides the normal relationship between CDH11 and smooth muscle alpha-actin to exacerbate the myofibroblast disease phenotype. This phenotypic switch is potentiated through the IL-6 signaling axis and could act as a paracrine mechanism of myofibroblast activation in neighboring aortic valve interstitial cells in a positive feedback loop. These data suggest CDH11 is an important mediator of the myolibroblast phenotype and identify several mechanisms by which it modulates cell behavior.NEW & NOTEWORTHY Cadherin-11 influences valvular interstitial cell contractility by regulating focal adhesions and inflammatory cytokine secretion. Transforming growth factor-beta(1) overrides the normal balance between cadherin-11 and smooth muscle alpha-actin expression to promote a myofibroblast phenotype. C.adherin-11 is necessary for IL-6 and chitinase-3-like protein 1 secretion, and IL-6 promotes contractility. Targeting cadherin-11 could therapeutically influence valvular interstitial cell phenotypes in a multifaceted manner.