Copper-Binding Domain Variation in a Novel Murine Lysyl Oxidase Model Produces Structurally Inferior Aortic Elastic Fibers Whose Failure Is Modified by Age, Sex, and Blood Pressure

Kit Man Tsang, Russell H. Knutsen, Charles J. Billington, Eric Lindberg, Heiko Steenbock, Yi Ping Fu, Amanda Wardlaw-Pickett, Delong Liu, Daniela Malide, Zu Xi Yu, Christopher K.E. Bleck, Jürgen Brinckmann, Beth A. Kozel

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5 Scopus citations


Lysyl oxidase (LOX) is a copper-binding enzyme that cross-links elastin and collagen. The dominant LOX variation contributes to familial thoracic aortic aneurysm. Previously reported murine Lox mutants had a mild phenotype and did not dilate without drug-induced provocation. Here, we present a new, more severe mutant, Loxb2b370.2Clo (c.G854T; p.Cys285Phe), whose mutation falls just N-terminal to the copper-binding domain. Unlike the other mutants, the C285F Lox protein was stably produced/secreted, and male C57Bl/6J Lox+/C285F mice exhibit increased systolic blood pressure (BP; p < 0.05) and reduced caliber aortas (p < 0.01 at 100mmHg) at 3 months that independently dilate by 6 months (p < 0.0001). Multimodal imaging reveals markedly irregular elastic sheets in the mutant (p = 2.8 × 10−8 for breaks by histology) that become increasingly disrupted with age (p < 0.05) and breeding into a high BP background (p = 6.8 × 10−4). Aortic dilation was amplified in males vs. females (p < 0.0001 at 100mmHg) and ameliorated by castration. The transcriptome of young Lox mutants showed alteration in dexamethasone (p = 9.83 × 10−30) and TGFβ-responsive genes (p = 7.42 × 10−29), and aortas from older C57Bl/6J Lox+/C285F mice showed both enhanced susceptibility to elastase (p < 0.01 by ANOVA) and increased deposition of aggrecan (p < 0.05). These findings suggest that the secreted Lox+/C285F mutants produce dysfunctional elastic fibers that show increased susceptibility to proteolytic damage. Over time, the progressive weakening of the connective tissue, modified by sex and blood pressure, leads to worsening aortic disease.

Original languageEnglish (US)
Article number6749
JournalInternational journal of molecular sciences
Issue number12
StatePublished - Jun 1 2022

Bibliographical note

Funding Information:
Funding: This work was supported by the Division of Intramural Research of the National Heart Lung and Blood Institute of the NIH. ZIA HL006244.

Publisher Copyright:
© 2022 by the authors. Licensee MDPI, Basel, Switzerland.


  • aorta
  • collagen
  • elastin
  • Fib-SEM
  • genotype–phenotype correlation
  • lysyl oxidase
  • rare variant
  • sex as a biological variable
  • thoracic aortic aneurysm
  • two-photon
  • Blood Pressure
  • Mice, Inbred C57BL
  • Aorta/metabolism
  • Male
  • Elastic Tissue/metabolism
  • Animals
  • Female
  • Mice
  • Protein-Lysine 6-Oxidase/genetics
  • Copper
  • Dilatation, Pathologic/pathology

PubMed: MeSH publication types

  • Journal Article


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