Tgfβ-Smad and MAPK signaling mediate scleraxis and proteoglycan expression in heart valves.
Tgfβ-Smad and MAPK signaling mediate scleraxis and proteoglycan expression in heart valves.
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DOI：
10.1016/j.yjmcc.2013.10.007
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发表时间：
2013-12
影响因子：
5
通讯作者：
Lincoln, Joy
中科院分区：
文献类型：
--
作者：
Barnette, Damien N.;Hulin, Alexia;Ahmed, A. S. Ishtiaq;Colige, Alain C.;Azhar, Mohamad;Lincoln, Joy
成熟的心脏瓣膜是由三个高度组织化的细胞外基质层组成的复杂结构，所述细胞外基质层主要由胶原蛋白、蛋白聚糖和弹性蛋白组成。总的来说，这些不同的基质成分提供了瓣膜在整个生命周期中发挥功能所需的所有生物力学特性。与健康瓣膜相比，粘液瘤性瓣膜病是人群中二尖瓣脱垂的最常见原因，其特征在于瓣膜三层结构内蛋白聚糖异常丰富。尽管有临床意义，但这种表型的病因尚不清楚。Scleraxis（Scx）是一个基本的螺旋-环-螺旋转录因子，我们以前发现，在瓣膜形成的重塑阶段建立心脏瓣膜结构所需。在这项研究中，我们报告说，重塑心脏瓣膜从Scx空小鼠表达蛋白多糖，特别是硫酸软骨素蛋白多糖（CSPGs）的水平下降，而在胚胎禽瓣膜前体细胞和成年猪瓣膜间质细胞的过度表达增加CSPGs。使用这些系统，我们进一步确定Scx在此过程中受到典型Tgfβ2信号传导的正调控，并且这被MAPK活性减弱。最后，我们表明Scx在人类患者和小鼠模型的粘液瘤瓣膜中增加，并且人类二尖瓣间质细胞中的过表达适度增加了蛋白聚糖的表达，与粘液瘤二尖瓣表型一致。总之，这些研究确定了Scx在胚胎和成熟瓣膜细胞中调节蛋白聚糖的重要作用，并表明不平衡的调节可能影响粘液瘤的发病机制。
Mature heart valves are complex structures consisting of three highly organized extracellular matrix layers primarily composed of collagens, proteoglycans and elastin. Collectively, these diverse matrix components provide all the necessary biomechanical properties for valve function throughout life. In contrast to healthy valves, myxomatous valve disease is the most common cause of mitral valve prolapse in the human population and is characterized by an abnormal abundance of proteoglycans within the valve tri-laminar structure. Despite the clinical significance, the etiology of this phenotype is not known. Scleraxis (Scx) is a basic-helix-loop-helix transcription factor that we previously showed to be required for establishing heart valve structure during remodeling stages of valvulogenesis. In this study, we report that remodeling heart valves from Scx null mice express decreased levels of proteoglycans, particularly chondroitin sulfate proteoglycans (CSPGs), while overexpression in embryonic avian valve precursor cells and adult porcine valve interstitial cells increases CSPGs. Using these systems we further identify that Scx is positively regulated by canonical Tgfβ2 signaling during this process and this is attenuated by MAPK activity. Finally, we show that Scx is increased in myxomatous valves from human patients and mouse models, and overexpression in human mitral valve interstitial cells modestly increases proteoglycan expression consistent with myxomatous mitral valve phenotypes. Together, these studies identify an important role for Scx in regulating proteoglycans in embryonic and mature valve cells and suggest that imbalanced regulation could influence myxomatous pathogenesis.
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影响因子：
2.5
作者：
Azhar, Mohamad;Brown, Kristen;Gard, Connie;Chen, Hwudaurw;Rajan, Sudarsan;Elliott, David A.;Stevens, Mark V.;Camenisch, Todd D.;Conway, Simon J.;Doetschman, Thomas
通讯作者：
Doetschman, Thomas
DOI：
10.1126/science.1192149
发表时间：
2011-04-15
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Holm TM;Habashi JP;Doyle JJ;Bedja D;Chen Y;van Erp C;Lindsay ME;Kim D;Schoenhoff F;Cohn RD;Loeys BL;Thomas CJ;Patnaik S;Marugan JJ;Judge DP;Dietz HC
通讯作者：
Dietz HC
影响因子：
11.4
作者：
Bueno, OF;De Windt, LJ;Molkentin, JD
通讯作者：
Molkentin, JD
影响因子：
4.8
作者：
Lorda-Diez, Carlos I.;Montero, Juan A.;Hurle, Juan M.
通讯作者：
Hurle, Juan M.
影响因子：
20.1
作者：
Krenz, M;Yutzey, KE;Robbins, J
通讯作者：
Robbins, J