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Abstract: FR-PO708

The Role of Heme-Degrading and Heme-Binding Proteins in Decreasing Thrombosis

Session Information

Category: Dialysis

  • 704 Dialysis: Vascular Access

Authors

  • Nath, Meryl C., Mayo Clinic , Rochester, Minnesota, United States
  • Croatt, Anthony J., Mayo Clinic , Rochester, Minnesota, United States
  • Grande, Joseph P., Mayo Clinic , Rochester, Minnesota, United States
  • Ackerman, Allan W., Mayo Clinic , Rochester, Minnesota, United States
  • Belcher, John D., University of Minnesota, Minneaplis, Minnesota, United States
  • Regan, Raymond F., Thomas Jefferson University , Philadelphia, Pennsylvania, United States
  • Vercellotti, Gregory M., University of Minnesota, Minneaplis, Minnesota, United States
  • Nath, Karl A., Mayo Clinic , Rochester, Minnesota, United States
Background

Induction of the heme-degrading enzyme, heme oxygenase-1 (HO-1), protects against dysfunction and closure of an arteriovenous fistula (AVF) and other types of vascular injury. Thrombosis contributes to AVF dysfunction and closure, and to certain types of vascular and renal injury. The present study examined whether HO-1 induction or administration of its products reduces thrombosis in vivo.

Methods

We employed the murine clot model induced by infra-renal ligation (L) of the inferior vena cava (IVC). Clot size is assessed in this model by determining the clot weight/clot length ratio. Our prior studies in this model demonstrated that HO-1 is induced, and that clot size is increased in HO-1-/- mice as compared with HO-1+/+ mice.

Results

Clot size in the IVCL model was significantly reduced in mice treated with hemin (an inducer of HO-1) as compared with saline on day 1 (1.13±0.54 vs 2.92±0.21), day 2 (1.72±0.26 vs 3.58±0.36 ), and day 3 (1.70±0.47 vs 3.29±0.24) after IVCL. These beneficial effects of hemin were accompanied by reduced expression of proinflammatory and thrombogenic genes. We confirmed marked induction of HO-1 mRNA and protein and HO activity in the IVC in hemin-treated mice. HO-1 upregulation in the IVC by adeno-associated viral delivery also reduced clot size in the IVCL model. Biliverdin, a product of HO activity, reduced clot size on day 2 after IVCL, as did another product of HO activity, carbon monoxide, delivered as CORM-3. The constitutive HO isoform, HO-2, did not exhibit the anti-thrombotic efficacy of HO-1 as clot size was not increased in HO-2-/- mice as compared with HO-2+/+ mice. Analysis of the clot model further demonstrated that the heme-binding protein, hemopexin (HPX) was induced in the IVC, and that clot size was increased in HPX-/- mice as compared with HPX+/+ mice.

Conclusion

HO-1 and its products are markedly effective in inhibiting thrombosis, whereas such efficacy is not exhibited by HO-2. The beneficial effect of HO-1 in reducing AVF closure and vascular injury likely reflects, at least in part, its inhibitory effect on thrombogenesis. HPX is identified as a novel inhibitor of thrombogenesis in the IVCL model.

Funding

  • NIDDK Support