[273-POS]: Sulfasalazine reduces the toxins of preeclampsia soluble Flt1 and soluble endoglin and quenches endothelial dysfunction in primary human tissues: A novel potential therapeutic.

OBJECTIVES: Sulfasalazine is an anti-inflammatory and immune modulating drug. Its mode of action has remained elusive, however recent evidence suggests it induces potent antioxidant enzyme heme-oxygenase1 (HO1) via nuclear erythroid-2-related factor 2 (Nrf2). Given its anti-oxidant capacity and that it is safe in pregnancy, we examined the potential for sulfasalazine as a novel therapeutic for preeclampsia. In particular, we examined its ability to quench anti-angiogenic factors sFlt1 and soluble endoglin (sEng) and reverse endothelial dysfunction in vitro.

METHODS: Increasing doses of sulfasalazine were administered to primary human umbilical vein endothelial cells (HUVECs) and sFlt1 and sEng release assessed. To induce endothelial dysfunction, HUVECs were treated with TNFα and the effect of sulfasalazine on monocyte adhesion determined. Finally the effect of sulfasalazine on HUVEC migration and proliferation was assessed.

RESULTS: Excitingly, we observed a significant dose dependent reduction in both sFlt1 and sEng release. Importantly, mRNA expression of newly described human and placental specific variant sFlt1-e15a mRNA was significantly decreased, as was MMP14 mRNA expression (MMP14 is the protease that produces sEng). As expected, sulfasalazine also significantly increased mRNA expression of HO-1. Treatment of HUVECs with TNFα induced significant upregulation of VCAM which was potently reversed by Sulfasalazine, indicating its ability to quench endothelial dysfunction. Furthermore, sulfalsazine significantly reduced monocyte adhesion to HUVECs treated with TNFα, again supporting its anti-inflammatory properties. Finally we demonstrated that sulfasalazine could reverse the negative effects of sFlt1 on VEGF-stimulated HUVEC migration, and enhance HUVEC proliferation.

CONCLUSIONS: Sulfasalazine is a novel agent, safe in pregnancy that significantly quenches sFlt1 and sEng release from human endothelial cells. In addition, it significantly reduces endothelial dysfunction and enhances endothelial cell migration and proliferation. This provides strong evidence to suggest that sulfasalazine may be able to quench the endothelial dysfunction of preeclampsia and could be an effective treatment for preeclampsia.

DISCLOSURES: F.C. Brownfoot: None. S. Tong: None. N. Hannan: None. R. Hastie: None. P. Cannon: None. T.J. Kaitu'u-Lino: None.