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Intracellular retention of mutant lysyl oxidase leads to aortic dilation in response to increased hemodynamic stress
Vivian S. Lee, … , Nathan O. Stitziel, Robert P. Mecham
Vivian S. Lee, … , Nathan O. Stitziel, Robert P. Mecham
Published August 8, 2019; First published June 18, 2019
Citation Information: JCI Insight. 2019;4(15):e127748. https://doi.org/10.1172/jci.insight.127748.
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Categories: Research Article Cell biology Vascular biology

Intracellular retention of mutant lysyl oxidase leads to aortic dilation in response to increased hemodynamic stress

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Abstract

Heterozygous missense mutations in lysyl oxidase (LOX) are associated with thoracic aortic aneurysms and dissections. To assess how LOX mutations modify protein function and lead to aortic disease, we studied the factors that influence the onset and progression of vascular aneurysms in mice bearing a Lox mutation (p.M292R) linked to aortic dilation in humans. We show that mice heterozygous for the M292R mutation did not develop aneurysmal disease unless challenged with increased hemodynamic stress. Vessel dilation was confined to the ascending aorta, although in both ascending and descending aortae, changes in vessel wall structure, smooth muscle cell number, and inflammatory cell recruitment differed between WT and mutant animals. Studies with isolated cells revealed that M292R-mutant LOX is retained in the endoplasmic reticulum and ultimately cleared through an autophagy/proteasome pathway. Because the mutant protein does not transit to the Golgi, where copper incorporation occurs, the protein is never catalytically active. These studies show that the M292R mutation results in LOX loss of function due to a secretion defect that predisposes the ascending aorta in mice (and by extension humans with similar mutations) to arterial dilation when exposed to risk factors that impart stress to the arterial wall.

Authors

Vivian S. Lee, Carmen M. Halabi, Thomas J. Broekelmann, Philip C. Trackman, Nathan O. Stitziel, Robert P. Mecham

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Figure 2

Ang II treatment leads to changes in vascular cellularity and infiltration of immune cells.

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Ang II treatment leads to changes in vascular cellularity and infiltrati...
(A) Frozen sections of descending aorta from Lox+/+ and Lox+/Mu animals following 28 days of treatment with Ang II or saline (asterisks indicate vessel lumen; scale bars: 5 μm). Macrophages (stained green, arrowheads) were detected with an antibody to CD68, and cell nuclei were visualized with DAPI. Red is elastin autofluorescence. The vessel wall was thicker in both Lox+/+ and Lox+/Mu animals following Ang II treatment, with more DAPI+ and CD68+ cells in the adventitia of both genotypes. (B) In the medial layer, there were fewer SMCs in the aorta of WT animals treated with Ang II but more cells in Lox+/Mu aorta. Shown are the mean ± SD for cell number counts between the internal and external elastic lamina on 7 tissue sections from each group. Two-way ANOVA with Tukey’s multiple-comparisons test, with the 2 variables being genotype and treatment, was used to assess differences. Data are presented as mean ± SD. *P < 0.05, **P < 0.01. (C) Medial CD68+ cells were mostly located on the luminal side of the media in the Lox+/+ aorta but nearer the adventitia in Lox+/Mu aorta after Ang II treatment.
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