Abstract 11846: Heme oxygenase-1/Carbon Monoxide (HO-1/CO) Promotes Thrombus Resolution by Down-Regulating Von Willebrand Factor and P-selectin in a Murine Model of Venous Thrombosis
Background: DVT is a major cause of cardiovascular morbidity and mortality in United States.HO-1/CO has anti-inflammatory and anticoagulant properties by augmenting fibrinolysis and inhibiting platelet aggregation.Vascular injury activates endothelial cells promotes expression of VWF and P-sel on EC during stasis-induced DVT.However,whether HO-1/CO, P-sel and vWF plays a role in platelet recruitment in DVT remains elusive.We hypothesize that HO-1/CO modulates venous thrombosis through a combination of anti-inflammatory and anti-thrombotic effects in part through suppressive effects on vWF and P-sel expression.
Methods: HO-1+/+ and HO-1-/- mice underwent IVC-ligation for 48 hrs. WT animals were also exposed to 250ppm of CO for 10 days post-thrombus induction.We examined serum levels of sP-sel and svWF.Inflammatory cytokine levels were measured in the venous wall via ELISA and qRT-PCR.Flow cytometry was used to measure expression of platelet and leukocyte markers.
Results: Compared to HO-1+/+, thrombus weights increased significantly in HO-1 -/- mice (5.6±.15vs.3.5±.19, n=6, p<0.0001, respectively).CO treatment had a modest inhibitory effect on thrombus weight. We also showed significant increase in sP-Sel (32.1% n=7, p<0.001) and svWF (57.9% n=7, p<0.001) levels in HO-1-/- DVT mice compared to sham operated HO-1-/- mice (Fig 1).There was also a significant increase in sP-sel and svWF levels in IVC-ligated HO-1+/+ mice compared to sham-operated mice (n=10, p=0.0002). Additionally,compared to IVC-ligated HO-1+/+ mice,platelet-leukocyte aggregates significantly increased in IVC-ligated HO-1-/- null mice (98.8% vs.71.8%, n=10, p=0.0166).Furthermore,the application of low-dose CO for 10 days after IVC-ligation decreased expression of sPsel (by 38%, n=5, p<0.05) and svWF (by 77%, n=5, p<0.05).
Conclusion: DVT strongly induce HO-1, actions of which may mitigate inflammatory upregulation of leukocyte adhesion receptors such as P-sel and vWF.
- © 2012 by American Heart Association, Inc.