TY - JOUR
T1 - Intracellular retention of mutant lysyl oxidase leads to aortic dilation in response to increased hemodynamic stress
AU - Lee, Vivian S.
AU - Halabi, Carmen M.
AU - Broekelmann, Thomas J.
AU - Trackman, Philip C.
AU - Stitziel, Nathan O.
AU - Mecham, Robert P.
N1 - Funding Information:
This work was supported by NIH grants R01HL53325, HL105314 (RPM), R21AR072748 (PCT), and R01HL131961 (NOS). Funds were also provided to RPM by the Ines Mandl Research Foundation. VSL was supported by training grant T32 HL125241 and a Predoctoral Individual National Research Service Award (F31HL136073). CMH was supported by NIH grant K08 HL135400. We thank Robyn Roth for assistance with electron microscopy and gratefully acknowledge assistance from James Fitzpatrick and staff at the Washington University Center for Cellular Imaging (WUCCI), which is supported by Washington University School of Medicine, the Children’s Discovery Institute of Washington University and St. Louis Children’s Hospital (CDI-CORE-2015-505), and the Foundation for Barnes-Jewish Hospital (grant no. 3770). Additionally, we thank Michael Wallendorf of the Washington University Division of Biostatistics for assistance with statistical data analysis.
Funding Information:
This work was supported by NIH grants R01HL53325, HL105314 (RPM), R21AR072748 (PCT), and R01HL131961 (NOS). Funds were also provided to RPM by the Ines Mandl Research Foundation. VSL was supported by training grant T32 HL125241 and a Predoctoral Individual National Research Service Award (F31HL136073). CMH was supported by NIH grant K08 HL135400. We thank Robyn Roth for assistance with electron microscopy and gratefully acknowledge assistance from James Fitzpatrick and staff at the Washington University Center for Cellular Imaging (WUCCI), which is supported by Washington University School of Medicine, the Children?s Discovery Institute of Washington University and St. Louis Children?s Hospital (CDI-CORE-2015-505), and the Foundation for Barnes-Jewish Hospital (grant no. 3770). Additionally, we thank Michael Wallendorf of the Washington University Division of Biostatistics for assistance with statistical data analysis.
Publisher Copyright:
© 2019, American Society for Clinical Investigation.
PY - 2019/8/8
Y1 - 2019/8/8
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85070823041&partnerID=8YFLogxK
U2 - 10.1172/jci.insight.127748
DO - 10.1172/jci.insight.127748
M3 - Article
C2 - 31211696
AN - SCOPUS:85070823041
SN - 2379-3708
VL - 4
JO - JCI Insight
JF - JCI Insight
IS - 15
M1 - :e127748
ER -