6-OR

Abstract

Objectives Key pathophysiological steps in preeclampsia (PE) are (1) release of anti-angiogenic factors sFlt-1 and soluble endoglin (sEng), (2) oxidative stress and (3) maternal endothelial dysfunction. We performed functional studies in primary human tissues to examine whether proton pump inhibitors (PPIs) can counter these pathophysiological effects. Methods Functional studies were performed on: (1) primary trophoblast, (2) primary human umbilical vein endothelial cells (HUVEC), (3) uterine microvascular cells and (4) placental explants, obtained from women with severe PE. Five PPIs (including esomeprazole, rabeprazole, lansoprazole) were added at increasing doses (0-100μM), and the following outputs examined: (1) sFlt-1/sEng production, (2) heme-oxygenase-1 (HO-1) expression and Nrf2 translocation and (3) endothelial dysfunction (modeled by adding TNFα or PE patient serum to endothelial cells). Results PPIs caused a dose-dependent reduction in mRNA expression of sFlt-1 variants (e15a and i13) and reduced secretion of sFlt1 and sEng in all cell types. The decrease was potent: for example the top dose of esomeprazole decreased sFlt-1 release from trophoblast by 50%, and sEng release by 70%. In contrast, pravastatin at the same dose did not decrease sFlt-1/sEng production. All PPIs induced a highly significant dose dependent increase in HO-1 mRNA and protein in all tissues. PPIs also induced nuclear translocation of the master antioxidant transcription factor, Nrf2, and upregulated Nrf2 regulated genes. Importantly, PPIs markedly reduced sFlt-1 production (and increased HO-1) when added to placental explants from women with severe PE. PPIs rescued both TNFα and PE serum induced endothelial dysfunction (quenching leukocyte adhesion and attenuating VCAM1 and endothelin-1 expression). Furthermore, PPIs blocked TNFα-induced disruption of endothelial tube formation (both in HUVECs and uterine microvascular cells). Conclusions PPIs potently decrease sFlt-1/sEng release, switch on anti-oxidant defenses and quench endothelial dysfunction. Widely prescribed for gastric reflux during pregnancy, they represent an exciting novel candidate therapeutic to treat severe preeclampsia. Disclosures K. Onda: None. N. Hannan: None. S. Beard: None. N. Binder: None. F. Brownfoot: None. T. Kaitu’u-Lino: None. L. Tuohey: None. R. Hastie: None. S. Tong: None.