Fibulin-4 conducts proper elastogenesis via interaction with cross-linking enzyme lysyl oxidase.
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.
Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, 606-8507, Japan.
Masahito
M
Horiguchi
Tadashi
T
Inoue
Tetsuya
T
Ohbayashi
Maretoshi
M
Hirai
Kazuo
K
Noda
Lihua Y
LY
Marmorstein
Daisuke
D
Yabe
Kyoko
K
Takagi
Tomoya O
TO
Akama
Toru
T
Kita
Takeshi
T
Kimura
Tomoyuki
T
Nakamura
D000818:Animals; D001158:Arteries / Q000378:metabolism* / Q000648:ultrastructure; D004549:Elastin / Q000378:metabolism*; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism*; D017353:Gene Deletion; D007150:Immunohistochemistry; D051379:Mice; D018345:Mice, Knockout; D008854:Microscopy, Electron; D016133:Polymerase Chain Reaction; D011485:Protein Binding; D008249:Protein-Lysine 6-Oxidase / Q000378:metabolism*
C403672:EFEMP2 protein, human; D016326:Extracellular Matrix Proteins; D004549:Elastin; D008249:Protein-Lysine 6-Oxidase