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(Circulation. 2007;115:1789-1797.)
© 2007 American Heart Association, Inc.

Molecular Cardiology

Negative Regulation of Soluble Flt-1 and Soluble Endoglin Release by Heme Oxygenase-1

Melissa Cudmore, PhD; Shakil Ahmad, PhD; Bahjat Al-Ani, PhD; Takeshi Fujisawa, PhD; Heather Coxall, BSc; Kunal Chudasama, BSc; Luke R. Devey, MD; Stephen J. Wigmore, MD; Allyah Abbas; Peter W. Hewett, PhD; Asif Ahmed, PhD

From the Departments of Reproductive and Vascular Biology (M.C., S.A., B.A.-A., T.F., H.C., K.C., A. Abbas, P.W.H., A. Ahmed) and Liver Research Group (L.R.D., S.J.W.), Institute of Biomedical Research, The Medical School, University of Birmingham, and Birmingham Women’s Hospital (M.C., S.A., B.A.-A., T.F., H.C., K.C., A. Abbas, P.W.H., A. Ahmed), Edgbaston, Birmingham, UK.

Correspondence to Dr Asif Ahmed, Department of Reproductive and Vascular Biology, Medical School, University of Birmingham, Edgbaston, Birmingham, West Midlands, B15 2TT, UK. E-mail a.s.ahmed{at}bham.ac.uk

Received August 23, 2006; accepted January 19, 2007.

Background— Preeclampsia is characterized clinically by hypertension and proteinuria. Soluble Flt-1 (sFlt-1; also known as soluble vascular endothelial growth factor receptor-1 [VEGFR-1]) and soluble endoglin (sEng) are elevated in preeclampsia, and their administration to pregnant rats elicits preeclampsia-like symptoms. Heme oxygenase-1 (HO-1) and its metabolite carbon monoxide (CO) exert protective effects against oxidative stimuli. Thus, we hypothesized that HO-1 upregulation may offer protection against preeclampsia by inhibiting sFlt-1 and sEng release.

Methods and Results— Preeclamptic villous explants secreted high levels of sFlt-1 and sEng. Adenoviral overexpression of HO-1 in endothelial cells inhibited VEGF-mediated sFlt-1 release and interferon-– and tumor necrosis factor-–induced sEng release, whereas HO-1 inhibition potentiated sFlt-1 and sEng production from endothelial cells and placental villous explants. Consistent with these findings, mice lacking HO-1 produced higher levels of sFlt-1 and sEng compared with wild-type mice. Using selective ligands (VEGF-E and placental growth factor) and a receptor-specific inhibitor (SU-1498), we demonstrated that VEGF-induced sFlt-1 release was VEGFR-2 dependent. Furthermore, CO–releasing molecule-2 (CORM-2) or CO decreased sFlt-1 release and inhibited VEGFR-2 phosphorylation. Treatment of endothelial cells with statins upregulated HO-1 and inhibited the release of sFlt-1, whereas vitamins C and E had no effect.

Conclusions— The present study demonstrates that the HO-1/CO pathway inhibits sFlt-1 and sEng release, providing compelling evidence for a protective role of HO-1 in pregnancy, and identifies HO-1 as a novel target for the treatment of preeclampsia.

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