Preeclampsia (PE) is a major complication of pregnancy, responsible for ~ 60,000 maternal deaths per year and far greater rates of perinatal death. Currently there is no treatment. The key pathophysiological aspects of PE are 1) oxidative stress 2) release of the anti-angiogenic factors sFlt1 and sEng into the maternal circulation and 3) maternal endothelial dysfunction. A drug that counters these effects could be an effective PE therapeutic. Proton Pump Inhibitors (PPIs), used for gastric reflux treatment, have potent antioxidant/antiinflammatory properties. We examined whether PPIs may be a potential treatment for PE.
Functional studies were performed on 1) isolated primary trophoblast 2) primary human umbilical vein endothelial cells (HUVEC) and 3) uterine microvascular cells. The effects of five PPIs were tested at increasing doses (0-100μM) and the following outputs examined 1) heme-oxygenase-1 expression (HO-1, key antioxidant enzyme) and transcription factor, Nrf2 nuclear translocation 2) secretion of sFlt1 and sEng, 3) endothelial dysfunction and 4) endothelial tube forming assays.
All PPIs induced highly significant dose dependent increases in HO-1 mRNA and protein. PPIs induced nuclear translocation of the master antioxidant transcription factor Nrf2, and upregulated Nrf2 responsive genes. PPIs caused a significant dose-dependent decrease in the secretion of the anti-angiogenic factors, sFlt1 and sEng in all three cell types. Models of endothelial dysfunction were induced in vitro by addition of either TNFα or PE serum; markers of endothelial dysfunction (VCAM1 and endothelin-1 mRNA/protein) were significantly reduced with PPIs dose dependently. Furthermore PPIs decreased leukocyte adhesion to endothelial cells and rescued TNFα induced disruption to endothelial tube formation assays.
Summary and conclusions:
In primary human tissues, PPIs potently quenched the pathophysiological characteristics of preeclampsia. Thus, PPIs represent an exciting novel candidate therapeutic for severe preeclampsia. Given they are safe in pregnancy, PPIs could be fast-tracked to clinical trials.