Negative regulation of soluble Flt-1 and soluble endoglin release by heme oxygenase-1

Autor: Shakil Ahmad, Stephen J. Wigmore, Bahjat Al-Ani, Asif Ahmed, Allyah Abbas, Kunal Chudasama, Peter W. Hewett, Takeshi Fujisawa, Luke Devey, Melissa J. Cudmore, Heather Coxall
Rok vydání: 2007
Předmět:
Vascular Endothelial Growth Factor A
Angiogenesis
Swine
Placenta
Pregnancy Proteins
Antioxidants
Culture Media
Serum-Free
chemistry.chemical_compound
Mice
Pre-Eclampsia
Pregnancy
RNA
Small Interfering
Heme
Cells
Cultured
Mice
Knockout
Carbon Monoxide
Endoglin
Cell Hypoxia
Vascular endothelial growth factor
medicine.anatomical_structure
embryonic structures
Female
Cardiology and Cardiovascular Medicine
medicine.medical_specialty
Endothelium
Recombinant Fusion Proteins
Genetic Vectors
Receptors
Cell Surface
Oxidative phosphorylation
Preeclampsia
Interferon-gamma
Organ Culture Techniques
Downregulation and upregulation
Antigens
CD
Physiology (medical)
Internal medicine
medicine
Organometallic Compounds
Animals
Humans
Placenta Growth Factor
Vascular Endothelial Growth Factor Receptor-1
business.industry
Tumor Necrosis Factor-alpha
Endothelial Cells
medicine.disease
Vascular Endothelial Growth Factor Receptor-2
Rats
Heme oxygenase
Oxidative Stress
Endocrinology
chemistry
Solubility
Heme Oxygenase (Decyclizing)
Endothelium
Vascular
Hydroxymethylglutaryl-CoA Reductase Inhibitors
business
Heme Oxygenase-1
Zdroj: Circulation. 115(13)
ISSN: 1524-4539
Popis: 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-γ– and tumor necrosis factor-α–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.
Databáze: OpenAIRE
Externí odkaz: