A matricellular protein fibulin-4 is essential for the activation of lysyl oxidase.
Function
Has a role in extracellular matrix assembly, where it is essential for the activity of LOX (Lysyl oxidase enzyme). Required for the transfer of copper ion from copper transporter ATP7A to LOX in the trans-golgi network. This is an important step in the formation of lysine tyrosyl quinone (LTQ), an essential LOX cofactor.
In fibulin-4 mutant mice altered mitochondrial function and metabolic dysregulation leading to increased ROS levels and altered energy production may contribute to thoracic aortic aneurysm formation via PGC1A regulation., Decreased mitochondrial respiration without changes in expression or activity of mitochondrial complex proteins and increased reactive oxygen species. Mediated via increased TGF-beta signaling and reduced PGC1-a levels.
Function
In mutant mice with 4-fold reduction in FBLN-4 protein, altered mitochondrial function and metabolic dysregulation.
These data clearly establish a functional link between Ltbp-4L and fibulin-4 as a crucial molecular requirement for survival and elastogenesis in mice.
These data provide new insights in the molecular interaction between Fibulin-4 and TGF-beta pathway regulation in the pathogenesis of aortic aneurysms.
Compared to control SMCs the modulus of Eln-/- SMCs is reduced by 40% but is unchanged in Fbln4-/- SMCs. The Eln-/- SMC modulus is rescued by soluble or alpha elastin treatment.
Data show that fibulin-4 staining intensity in the ligamentum flavum was greatest at P14 though moderately strong at P7 and P21 and efore P7 and after P28 staining was detectable but relatively minimal.
Data show that the structural and functional alterations were accompanied by upregulation of TGF-beta signaling in aortas from fibulin-4 deficient mice.
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