Fibulin-1 is required during cardiac ventricular morphogenesis for versican cleavage, suppression of ErbB2 and Erk1/2 activation, and to attenuate trabecular cardiomyocyte proliferation.
Fibulin-1 is required during cardiac ventricular morphogenesis for versican cleavage, suppression of ErbB2 and Erk1/2 activation, and to attenuate trabecular cardiomyocyte proliferation.
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DOI：
10.1002/dvdy.23716
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发表时间：
2012-02
影响因子：
2.5
通讯作者：
Argraves, W. Scott
中科院分区：
文献类型：
--
作者：
Cooley, Marion A.;Fresco, Victor M.;Dorlon, Margaret E.;Twal, Waleed O.;Lee, Nathan V.;Barth, Jeremy L.;Kern, Christine B.;Iruela-Arispe, M. Luisa;Argraves, W. Scott
关键词：
小梁形成是心室形态发生的组成部分，并依赖于基质金属蛋白酶ADAMTS 1。ADAMTS 1的底物是蛋白聚糖多功能蛋白聚糖，其在发育中的心室中表达，并与小梁形成有关。Fibulin-1是心室形态发生所需的多功能蛋白聚糖和ADAMTS 1结合细胞外基质蛋白。在这里，我们研究了fibulin-1在体外ADAMTS 1介导的多功能蛋白聚糖裂解的参与，以及fibulin-1在心室形态发生中多功能蛋白聚糖裂解的参与。我们发现，fibulin-1是一个辅助因子ADAMTS 1依赖的多功能蛋白聚糖V1的体外切割，产生一个70 kDa的氨基末端片段。此外，发现小鼠中的fibulin-1缺陷导致心室70-kDa多功能蛋白聚糖V1切割产物水平的显著降低（>90%）和小梁心肌细胞增殖的2倍增加。在fibulin-1缺失的心脏中，多功能蛋白聚糖V1裂解减少和小梁心肌细胞增殖增加伴随着ErbB 2和Erk 1/2的心室激活增加。相反，多功能蛋白聚糖缺乏导致心肌细胞增殖减少和心室小梁形成减少。我们的结论是，fibulin-1调节versican依赖性事件在心室形态发生促进ADAMTS 1切割versican导致抑制小梁心肌细胞增殖介导的ErbB 2-地图激酶途径。
Trabeculation is an integral component of cardiac ventricular morphogenesis and is dependent on the matrix metalloproteinase, ADAMTS1. A substrate of ADAMTS1 is the proteoglycan versican which is expressed in the developing ventricle and which has been implicated in trabeculation. Fibulin-1 is a versican and ADAMTS1-binding extracellular matrix protein required for ventricular morphogenesis. Here we investigated the involvement of fibulin-1 in ADAMTS1-mediated cleavage of versican in vitro, and the involvement of fibulin-1 in versican cleavage in ventricular morphogenesis. We show that fibulin-1 is a cofactor for ADAMTS1-dependent in vitro cleavage of versican V1, yielding a 70-kDa amino-terminal fragment. Furthermore, fibulin-1-deficiency in mice was found to cause a significant reduction (>90%) in ventricular levels of the 70-kDa versican V1 cleavage product and a 2-fold increase in trabecular cardiomyocyte proliferation. Decreased versican V1 cleavage and augmented trabecular cardiomyocyte proliferation in fibulin-1 null hearts is accompanied by increased ventricular activation of ErbB2 and Erk1/2. By contrast, versican deficiency was found to lead to decreased cardiomyocyte proliferation and reduced ventricular trabeculation. We conclude that fibulin-1 regulates versican-dependent events in ventricular morphogenesis by promoting ADAMTS1 cleavage of versican leading to suppression of trabecular cardiomyocyte proliferation mediated by the ErbB2-Map kinase pathway.
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影响因子：
20.1
作者：
Henderson, DJ;Copp, AJ
通讯作者：
Copp, AJ
影响因子：
4.8
作者：
Rodríguez-Manzaneque, JC;Milchanowski, AB;Iruela-Arispe, ML
通讯作者：
Iruela-Arispe, ML
影响因子：
15.9
作者：
Nakamura, Tomoki;Colbert, Melissa;Robbins, Jeffrey
通讯作者：
Robbins, Jeffrey
影响因子：
2.5
作者：
Kern, Christine B.;Norris, Russell A.;Mjaatvedt, Corey H.
通讯作者：
Mjaatvedt, Corey H.
影响因子：
64.8
作者：
GASSMANN, M;CASAGRANDA, F;LEMKE, G
通讯作者：
LEMKE, G