PMID- 29466360 OWN - NLM STAT- MEDLINE DCOM- 20180309 LR - 20181202 IS - 1932-6203 (Electronic) IS - 1932-6203 (Linking) VI - 13 IP - 2 DP - 2018 TI - Combining metformin and esomeprazole is additive in reducing sFlt-1 secretion and decreasing endothelial dysfunction - implications for treating preeclampsia. PG - e0188845 LID - 10.1371/journal.pone.0188845 [doi] LID - e0188845 AB - INTRODUCTION: The discovery of new treatments that prevent or treat preeclampsia would be a major advance. Antiangiogenic factors soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sENG) are secreted in excess from the placenta, causing hypertension, endothelial dysfunction, and multiorgan injury. We recently identified metformin and esomeprazole as potential treatments for preeclampsia. Both reduce placental and endothelial secretion of sFlt-1 and soluble endoglin, and reduce endothelial dysfunction. OBJECTIVES: We set out to assess whether combining metformin and esomeprazole would additively reduce sFlt-1 and soluble endoglin secretion and reduce endothelial dysfunction (verses drug alone). Metformin and esomeprazole were added to primary placental cells and tissues, and endothelial cells and their effects on sFlt-1 and soluble endoglin secretion were assessed in vitro. Tumor necrosis factor-alpha (TNF-alpha) was added to endothelial cells to induce dysfunction in vitro. We examined the ability of metformin + esomeprazole to rescue TNF-alpha induced vascular cell adhesion molecule-1 (VCAM-1) and Endothelin-1 (ET-1) expression, leukocyte adhesion (markers of endothelial dysfunction). RESULTS: Combining metformin and esomeprazole was additive at reducing sFlt-1 secretion and expression of sFlt-1 e15a mRNA isoform in primary cytotrophoblast, placental explants and endothelial cells. In contrast, no additive reduction in sENG was observed with combined metformin and esomeprazole. The low-dose combination of metformin + esomeprazole additively reduced TNF-alpha-induced VCAM-1 mRNA, but not VCAM-1 protein expression. There was no additive reduction when combining metformin and esomeprazole on TNF-alpha induced PBMC adhesion to endothelial cells. However, combining metformin and esomeprazole additively reduced ET-1 mRNA expression. CONCLUSIONS: In conclusion combining metformin and esomeprazole additively reduced secretion of sFlt-1, and markers of endothelial dysfunction. The combination of metformin and esomeprazole may provide a more effective treatment or prevention for preeclampsia compared to either as single agents. FAU - Kaitu'u-Lino, Tu'uhevaha J AU - Kaitu'u-Lino TJ AD - Translational Obstetrics Group, The Department of Obstetrics and Gynaecology, University of Melbourne and Mercy Perinatal, Mercy Hospital for Women, Heidelberg, Victoria, Australia. FAU - Brownfoot, Fiona C AU - Brownfoot FC AD - Translational Obstetrics Group, The Department of Obstetrics and Gynaecology, University of Melbourne and Mercy Perinatal, Mercy Hospital for Women, Heidelberg, Victoria, Australia. FAU - Beard, Sally AU - Beard S AD - Translational Obstetrics Group, The Department of Obstetrics and Gynaecology, University of Melbourne and Mercy Perinatal, Mercy Hospital for Women, Heidelberg, Victoria, Australia. FAU - Cannon, Ping AU - Cannon P AD - Translational Obstetrics Group, The Department of Obstetrics and Gynaecology, University of Melbourne and Mercy Perinatal, Mercy Hospital for Women, Heidelberg, Victoria, Australia. FAU - Hastie, Roxanne AU - Hastie R AD - Translational Obstetrics Group, The Department of Obstetrics and Gynaecology, University of Melbourne and Mercy Perinatal, Mercy Hospital for Women, Heidelberg, Victoria, Australia. FAU - Nguyen, Tuong V AU - Nguyen TV AD - Translational Obstetrics Group, The Department of Obstetrics and Gynaecology, University of Melbourne and Mercy Perinatal, Mercy Hospital for Women, Heidelberg, Victoria, Australia. FAU - Binder, Natalie K AU - Binder NK AD - Translational Obstetrics Group, The Department of Obstetrics and Gynaecology, University of Melbourne and Mercy Perinatal, Mercy Hospital for Women, Heidelberg, Victoria, Australia. FAU - Tong, Stephen AU - Tong S AD - Translational Obstetrics Group, The Department of Obstetrics and Gynaecology, University of Melbourne and Mercy Perinatal, Mercy Hospital for Women, Heidelberg, Victoria, Australia. FAU - Hannan, Natalie J AU - Hannan NJ AUID- ORCID: 0000-0001-8446-2250 AD - Translational Obstetrics Group, The Department of Obstetrics and Gynaecology, University of Melbourne and Mercy Perinatal, Mercy Hospital for Women, Heidelberg, Victoria, Australia. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20180221 PL - United States TA - PLoS One JT - PloS one JID - 101285081 RN - 9100L32L2N (Metformin) RN - EC 2.7.10.1 (FLT1 protein, human) RN - EC 2.7.10.1 (Vascular Endothelial Growth Factor Receptor-1) RN - N3PA6559FT (Esomeprazole) SB - IM MH - Endothelium, Vascular/*drug effects/physiopathology MH - Esomeprazole/*administration & dosage MH - Female MH - Human Umbilical Vein Endothelial Cells MH - Humans MH - Metformin/*administration & dosage MH - Pre-Eclampsia/*drug therapy MH - Pregnancy MH - Vascular Endothelial Growth Factor Receptor-1/*metabolism PMC - PMC5821305 COIS- Competing Interests: There are no competing interests. EDAT- 2018/02/22 06:00 MHDA- 2018/03/10 06:00 PMCR- 2018/02/21 CRDT- 2018/02/22 06:00 PHST- 2017/05/25 00:00 [received] PHST- 2017/11/14 00:00 [accepted] PHST- 2018/02/22 06:00 [entrez] PHST- 2018/02/22 06:00 [pubmed] PHST- 2018/03/10 06:00 [medline] PHST- 2018/02/21 00:00 [pmc-release] AID - PONE-D-17-20164 [pii] AID - 10.1371/journal.pone.0188845 [doi] PST - epublish SO - PLoS One. 2018 Feb 21;13(2):e0188845. doi: 10.1371/journal.pone.0188845. eCollection 2018.