Fibulin-4 conducts proper elastogenesis via interaction with cross-linking enzyme lysyl oxidase
Fibulin-4 conducts proper elastogenesis via interaction with cross-linking enzyme lysyl oxidase
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DOI：
10.1073/pnas.0908268106
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发表时间：
2009-11-10
影响因子：
11.1
通讯作者：
Nakamura, Tomoyuki
中科院分区：
文献类型：
--
作者：
Horiguchi, Masahito;Inoue, Tadashi;Nakamura, Tomoyuki
大动脉以及肺和皮肤都含有弹性纤维，是维持其生理功能的重要组成部分。尽管最近的研究表明糖蛋白fibulin-4（FBLN4）对于成熟弹性纤维的组装是必不可少的，但FBLN4如何参与弹性生成仍有待阐明。在这里，我们报告了 FBLN4 在动脉弹性纤维发育中的剂量依赖性需求，以及 FBLN4 在招募弹性蛋白交联酶赖氨酰氧化酶 (LOX) 中的特定作用。 Fbln4 表达减少是通过平滑肌特异性 Cre 介导的基因缺失实现的，导致动脉僵硬。电子显微镜检查显示杂乱的厚弹性层和弹性蛋白的异常沉积。当Fbln4表达水平降低至更低水平时，发现升主动脉出现动脉瘤性扩张，而全身性Fbln4缺失小鼠则因膈肌破裂而在围产期死亡。我们还发现 FBLN4 和 LOX 前肽之间存在特异性相互作用，可有效促进 LOX 组装到弹性蛋白原上。这些数据表明了一种弹性生成机制，其中足够量的 FBLN4 对于将 LOX 束缚到原弹性蛋白以促进交联至关重要。
Great arteries, as well as lungs and skin, contain elastic fibers as important components to maintain their physiological functions. Although recent studies have revealed that a glycoprotein fibulin-4 (FBLN4) is indispensable for the assembly of mature elastic fibers, it remains to be elucidated how FBLN4 takes part in elastogenesis. Here, we report a dose-dependent requirement for FBLN4 in the development of the elastic fibers in arteries, and a specific role of FBLN4 in recruiting the elastin-cross-linking enzyme, lysyl oxidase (LOX). Reduced expression of Fbln4, which was achieved with a smooth muscle-specific Cre-mediated gene deletion, caused arterial stiffness. Electron-microscopic examination revealed disorganized thick elastic laminae with aberrant deposition of elastin. Aneurysmal dilation of the ascending aorta was found when the Fbln4 expression level was reduced to an even lower level, whereas systemic Fbln4 null mice died perinatally from rupture of the diaphragm. We also found a specific interaction between FBLN4 and the propeptide of LOX, which efficiently promotes assembly of LOX onto tropoelastin. These data suggest a mechanism of elastogenesis, in which a sufficient amount of FBLN4 is essential for tethering LOX to tropoelastin to facilitate cross-linking.