Abstract: SA-OR094

Upregulation of Lysyl Oxidase Activity in Vascular Smooth Muscle Underlies Increased Vascular Stiffness in CKD

Session Information

Category: Hypertension

  • 1103 Vascular Biology and Dysfunction

Authors

  • Mohandas, Rajesh, University of Florida, Gainesville, Florida, United States
  • To, Brandon, University of Florida , Melbourne, Florida, United States
  • Hahn, William W, University of Florida , Melbourne, Florida, United States
  • Ferns, Philip, University of Florida , Melbourne, Florida, United States
  • Kilar, Cody, University of Florida , Melbourne, Florida, United States
  • Segal, Mark S., University of Florida, Gainesville, Florida, United States
Background

Introduction: Individuals with chronic kidney disease (CKD) have increased vascular stiffness which correlates with adverse cardiovascular outcomes and mortality. This increase in stiffness is thought to be a consequence of the metabolic derangements of CKD. However, our data shows that vascular smooth muscle dysfunction occurs early in CKD and is not completely explained by endothelial dysfunction. Lysyl oxidase is an amine oxidase that crosslinks collagen and elastin and contributes to stiffness of extracellular matrix. LOX is upregulated by reactive oxygen species, which is increased in CKD.

Hypothesis: We hypothesized that increased vascular stiffness in CKD is due to upregulation lysyl oxidase and increases in collagen and elastin cross linking.

Methods

Method: In vitro: Aortic smooth muscle cells were treated with serum from uremic patients or healthy controls. Lysyl oxidase mRNA and activity was measured by a colorimetricassay. In vivo: 6-8 week old C57BL6 mice were subject to a 5/6 nephrectomy model of CKD or sham surgery. 6 weeks later mice were sacrificed. Serum levels of lysyl oxidase were assayed.Mesenteric arteries were mounted in an arteriograph chamber and denuded of endothelium.Passive compliance was determined by measuring changes in luminal diameter to step wise increments in luminal pressure. Aortic smooth muscle lysates were assayed for lysyl oxidaseactivity.

Results

Results: Treatment with uremic serum resulted in an upregulation of lysyl oxidase in cell culture supernatant 22.5 vs 15.58 (n=6 p=0.001). Mice subjected to the CKD model demonstrated increased vascular stiffness. Aortic smooth muscle lysates demonstrated increased lysyl oxidase activity in CKD mice as compared to sham surgical controls [15.67 vs. 12.75 (n=5,p=0.02)]. There was no change in serum lysyl oxidase activity.

Conclusion

Conclusion: Upregulation of lysyl oxidase in vascular smooth muscle cells occurs early in CKD and may be a key mediator of increased vascular stiffness. Lysyl oxidase is a potential novel therapeutic target for CV disease in CKD.

Funding

  • Other NIH Support