Oxysterol-induced soluble endoglin release and its involvement in hypertension

Autor: Elena Llano, María González-Núñez, Carmen Langa, Carmelo Bernabeu, Antonio Castrillo, Mercedes Diaz, Barbara Oujo, Francisco J. Blanco, José M. López-Novoa, Ana C. Valbuena-Diez, Alberto M. Pendás
Přispěvatelé: Ministerio de Ciencia e Innovación (España), Fundación Genoma España, Instituto Reina Sofía de Investigación en Nefrología (España), Junta de Castilla y León, Centro de Investigación Biomédica en Red Enfermedades Raras (España), Red Temática de Investigación Cooperativa en Cáncer (España), Instituto de Salud Carlos III, European Commission
Rok vydání: 2012
Předmět:
Male
Agonist
medicine.medical_specialty
Placenta Diseases
Hydrocarbons
Fluorinated
Oxysterol
medicine.drug_class
Blood Pressure
Mice
Transgenic
Receptors
Cell Surface
Endogeny
Mice
Pre-Eclampsia
Antigens
CD
Ischemia
Pregnancy
Cell Line
Tumor
Physiology (medical)
Internal medicine
Human Umbilical Vein Endothelial Cells
Matrix Metalloproteinase 14
medicine
polycyclic compounds
Animals
Humans
Choriocarcinoma
Receptor
Liver X receptor
Liver X Receptors
Tissue Inhibitor of Metalloproteinase-3
chemistry.chemical_classification
Sulfonamides
Reactive oxygen species
business.industry
Anticholesteremic Agents
Endoglin
Intracellular Signaling Peptides and Proteins
Orphan Nuclear Receptors
Hydroxycholesterols
Mice
Inbred C57BL
Endocrinology
chemistry
Cell culture
Uterine Neoplasms
Female
lipids (amino acids
peptides
and proteins)
Cardiology and Cardiovascular Medicine
business
Zdroj: Digital.CSIC. Repositorio Institucional del CSIC
instname
Popis: [Background]: Ischemia in the placenta is considered the base of the pathogenesis of preeclampsia, a pregnancy-specific syndrome in which soluble endoglin (sEng) is a prognostic marker and plays a pathogenic role. Here, we investigated the effects of hypoxia and the downstream pathways in the release of sEng. [Methods and Results]: Under hypoxic conditions, the trophoblast-like cell line JAR showed an increase in sEng parallel to an elevated formation of reactive oxygen species. Because reactive oxygen species are related to the formation of oxysterols, we assessed the effect of 22-(R)-hydroxycholesterol, a natural ligand of the liver X receptor (LXR), and the LXR synthetic agonist T0901317. Treatment of JAR cells or human placental explants with 22-(R)-hydroxycholesterol or T0901317 resulted in a clear increase in sEng that was dependent on LXR. These LXR agonists induced an increased matrix metalloproteinase-14 expression and activity and a significant reduction of its endogenous inhibitor, tissue inhibitor of metalloproteinase-3. In addition, mice treated with LXR agonists underwent an increase in the plasma sEng levels, concomitant with an increase in arterial pressure. Moreover, transgenic mice overexpressing sEng displayed high blood pressure. Finally, administration of an endoglin peptide containing the consensus matrix metalloproteinase-14 cleavage site G-L prevented the oxysterol-dependent increase in arterial pressure and sEng levels in mice. [Conclusions]: These studies provide a clue to the involvement of the LXR pathway in sEng release and its pathogenic role in vascular disorders such as preeclampsia. © 2012 American Heart Association, Inc.
This work was supported by grants from the Ministerio de Ciencia e Innovación of Spain (SAF2010-61827 to Dr Bernabeu, SAF2011-29244 to Dr Castrillo, and SAF2010-15881 to Dr Lopez-Novoa), Genoma España (MEICA; Dr Bernabeu), Instituto Reina Sofía de Investigación Nefrológica (FRIAT; Dr Lopez-Novoa), Junta de Castilla and Leon (Excellence Group Grant GR-100 to Dr Lopez-Novoa), Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER; Dr Bernabeu), and Red de Investigación Cooperativa en Enfermedades Renales (REDINREN; Dr Lopez-Novoa). CIBERER and REDINREN are initiatives of the Instituto de Salud Carlos III of Spain supported by European Regional Development Funds (FEDER). The cardiovascular phenotyping unit, including the telemetry equipment, has been acquired with the support of FEDER. Dr Llano is recipient of a Ramón y Cajal Research contract.
Databáze: OpenAIRE
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