Abstract: SA-OR096

Targeting STUB1-Tissue Factor Axis Normalizes the Hyperthrombotic Uremic Phenotype without Increasing Bleeding Risk

Session Information

Category: Hypertension

  • 1103 Vascular Biology and Dysfunction

Authors

  • Shashar, Moshe, Boston University Medical Center, West Roxbury, Massachusetts, United States
  • Ravid, Katya, Boston University , Boston, Massachusetts, United States
  • Chitalia, Vipul C., Boston University School of Medicine, Boston, Massachusetts, United States
  • Belghasem, Mostafa, Boston University Medical Center, West Roxbury, Massachusetts, United States
  • Matsuura, Shinobu, Boston University Medical Center, West Roxbury, Massachusetts, United States
  • Alousi, Faisal F., Boston University Medical Center, West Roxbury, Massachusetts, United States
  • Rijal, Keshab, Boston University Medical Center, West Roxbury, Massachusetts, United States
  • Kolachalama, Vijaya B, Boston University School of Medicine, Boston, Massachusetts, United States
  • Henderson, Joel M., Boston University Medical Center, West Roxbury, Massachusetts, United States
  • Gautam, Amitabh, Boston Medical Center, Boston, Massachusetts, United States
  • Francis, Jean M., Boston University Medical Center, West Roxbury, Massachusetts, United States
Background

Atherothrombosis remains one of the major complications in CKD patients despite their treatment with antithrombotic/antiplatelet therapies. Though associations of uremic solutes (e.g. indolic solutes) and vascular wall protein, such as tissue factor (TF) and Aryl Hydrocarbon Receptor (AHR) have been defined, the specific mechanisms that drive the thrombotic and bleeding risks have not been fully understood, nor means by which they might be therapeutically manipulated. We further probed the uremic solute-AHR-TF axis for it’s role in uremic hyperthrombogenicity.

Methods

TF expression and activity and half-life were examined. Indoxyl sulfate was detected in animals using LC/MS approach. Adenine-induced CKD model and a novel uremic-solute injected mice were generated. Customized object-level intensity estimation algorithms were developed to quantify TF and carboxy terminus Hsc70 interacting protein (CHIP/STUB1) expressions in human arteriovenous fistulae (AVF) explants.

Results

We demonstrate that indolic solutes mediate the hyperthrombotic phenotype across all CKD stages in AHR- and TF-dependent manners in a mouse model in vivo. We demonstrate further that AHR regulates TF through STUB1, by interacting and degrading TF through ubiquitination, dependent on the uremic status. TF regulation by STUB1 is substantiated in humans by an inverse relationship between STUB1 and TF expression, and reduced STUB1-TF interaction in AVF explants. AHR and STUB1 modulations normalized the uremic hyperthrombotic phenotype to non-CKD range in both the animal models of CKD without prolonging the bleeding time. This finding is in stark contrast to Heparin, the standard-of-care antithrombotic in CKD patients

Conclusion

Our data implicate indolic solutes as bonafide mediators of the hyperthrombotic uremic milieu. Importantly, targeting the STUB1-TF axis reverses the thrombosis risk to the non-CKD range, importantly, without altering the hemostatic balance. Overall, we have significantly expanded the understanding of the interconnected relationships of thrombosis and hemostasis that drive the fragile thrombotic state in CKD.

Funding

  • Other NIH Support