Kidney Week

Abstract: SA-PO994

Lysyl Oxidase Insufficiency Exacerbates the Cardiovascular Phenotype Seen in a Mouse Model of Cutis Laxa

Session Information

• Hypertension and CVD: Mechanisms - II
  October 27, 2018 | Location: Exhibit Hall, San Diego Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Hypertension and CVD

• 1403 Hypertension and CVD: Mechanisms

Author

• Halabi, Carmen M., Washington University School of Medicine, Saint Louis, Missouri, United States

Carmen M. Halabi,

Background

Mutations in the elastogenic extracellular matrix protein Fibulin-4 (FBLN4) have been identified in humans with cutis laxa (ARCL 1B). Mice carrying the E57K mutation in Fbln4 recapitulate the cardiovascular phenotype observed in humans, including ascending aortic aneurysms and arterial tortuosity. Mutations in lysyl oxidase (LOX), the enzyme that crosslinks elastin, have recently been identified in patients with familial thoracic aortic aneurysms and dissection. The phenotypic similarities between mutant and knock-out mouse models of Fbln4 and Lox, in addition to in vitro data showing that FBLN4 promotes binding of pro-LOX to tropoelastin have led to the currently accepted hypothesis that FBLN4 facilitates elastin’s crosslinking by LOX. Whether this occurs in vivo is unclear however.

Methods

To determine whether FBLN4 interacts with LOX in the process of elastic fiber formation and arterial development, we bred recently characterized Fbln4^E57K mice to Lox hemizygous mice (Lox^+/-) and assessed the structural and functional effects of LOX insufficiency on the cardiovascular system of Fbln4^E57K mice.

Results

By 3-4 months of age Fbln4^E57K;Lox^+/- mice were similar in size to Fbln4^E57K mice and littermates. Ascending aortic aneurysms, which were incompletely penetrant and confined to the ascending aorta in Fbln4^E57K mice were significantly worsened by LOX insufficiency as they were fully penetrant and extended from the aortic root through the aortic arch in Fbln4^E57K;Lox^+/- mice. Additionally, arterial tortuosity and elastic fiber fragmentation of large conduit arteries were exacerbated by LOX insufficiency. Interestingly, muscular arteries remained intact. Fbln4^E57K;Lox^+/- mice had significant cardiac hypertrophy and widening of the pulse pressure that was due to lower diastolic blood compared to Fbln4^E57K mice.

Conclusion

In summary, LOX insufficiency exacerbated the vascular phenotype seen in mice with mutant FBLN4 suggesting that there is a functional interaction between the two molecules. Interestingly, elastic fiber formation was unaffected in muscular arteries raising the possibility that the process of elastic fiber assembly, previously thought to be the same in all elastic tissues, may differ between vascular beds. Further studies are underway to determine whether a direct interaction between FBLN4 and LOX occurs in the process of elastic fiber formation.

Funding

• Other NIH Support