Fibulin-4 conducts proper elastogenesis via interaction with cross-linking enzyme lysyl oxidase

Masahito Horiguchi, Tadashi Inoue, Tetsuya Ohbayashi, Maretoshi Hirai, Kazuo Noda, Lihua Y Marmorstein, Daisuke Yabe, Kyoko Takagi, Tomoya O. Akama, Toru Kita, Takeshi Kimura, Tomoyuki Nakamura

Research output: Contribution to journalArticle

90 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)19029-19034
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number45
DOIs
StatePublished - Nov 10 2009
Externally publishedYes

Fingerprint

Protein-Lysine 6-Oxidase
Elastic Tissue
Enzymes
Tropoelastin
Elastin
Arteries
Vascular Stiffness
Gene Deletion
Diaphragm
Smooth Muscle
Aorta
fibulin-4
Rupture
Dilatation
Glycoproteins
Electrons
Lung
Skin

Keywords

  • Development
  • Elastin
  • Extracellular matrix

ASJC Scopus subject areas

  • General

Cite this

Fibulin-4 conducts proper elastogenesis via interaction with cross-linking enzyme lysyl oxidase. / Horiguchi, Masahito; Inoue, Tadashi; Ohbayashi, Tetsuya; Hirai, Maretoshi; Noda, Kazuo; Marmorstein, Lihua Y; Yabe, Daisuke; Takagi, Kyoko; Akama, Tomoya O.; Kita, Toru; Kimura, Takeshi; Nakamura, Tomoyuki.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 106, No. 45, 10.11.2009, p. 19029-19034.

Research output: Contribution to journalArticle

Horiguchi, M, Inoue, T, Ohbayashi, T, Hirai, M, Noda, K, Marmorstein, LY, Yabe, D, Takagi, K, Akama, TO, Kita, T, Kimura, T & Nakamura, T 2009, 'Fibulin-4 conducts proper elastogenesis via interaction with cross-linking enzyme lysyl oxidase', Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 45, pp. 19029-19034. https://doi.org/10.1073/pnas.0908268106
Horiguchi, Masahito ; Inoue, Tadashi ; Ohbayashi, Tetsuya ; Hirai, Maretoshi ; Noda, Kazuo ; Marmorstein, Lihua Y ; Yabe, Daisuke ; Takagi, Kyoko ; Akama, Tomoya O. ; Kita, Toru ; Kimura, Takeshi ; Nakamura, Tomoyuki. / Fibulin-4 conducts proper elastogenesis via interaction with cross-linking enzyme lysyl oxidase. In: Proceedings of the National Academy of Sciences of the United States of America. 2009 ; Vol. 106, No. 45. pp. 19029-19034.
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