Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
George, M.
Liver X Receptor activation attenuates oxysterol induced
inflammatory responses and dysfunction in human fetoplacental
endothelial cells
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Medizinische Universität Graz; 2023. pp. 110
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- Autor*innen der Med Uni Graz:
- Betreuer*innen:
- Strobl Herbert
- Wadsack Christian
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- Abstract:
- Oxysterols are a family of sterols formed mostly by enzymatic cholesterol oxidation. Oxysterols can also be formed via non-enzymatic reactions both in vivo and ex vivo. Their systemic levels are found elevated in inflammatory pregnancy disorders such as gestational diabetes mellitus (GDM) and preeclampsia (PE). Oxysterols act through various intracellular and extracellular receptors, play diverse roles in regulating various physiological processes, and can have implications for human health and disease. Pregnancy disorders are often associated with chronic inflammation accompanied by altered inflammatory profiles in the mother, placenta, and fetus. Elevated levels of two oxysterols, namely, 7-ketocholesterol (7-ketoC) and 7β-hydroxycholesterol (7β-OHC), were observed in the cord blood of GDM offspring as well as in fetoplacental endothelial cells (fpEC). The main objective of this thesis was to investigate the impact of 7-ketoC and 7β-OHC on fetoplacental endothelial cells (fpEC). Subsequently, the effects of oxysterols on cellular mechanisms, such as endothelial dysfunction and their role in inflammation, were examined. Primary fpEC in culture, treated with 7-ketoC or 7β-OHC induced the activation of mitogen associated protein kinase (MAPK) and nuclear factor kappa B (NFκB) signaling which subsequently activated pro-inflammatory cytokines such as interleukin 6 (IL-6) and interleukin 8 (IL-8), and intercellular cell adhesion molecule-1 (ICAM-1). Furthermore, oxysterols elevatedintracellular calcium mobilization and reduced barrier impermeability by disrupting the VE-cadherin adherens junction, resulting in the formation of actin stress fibers and consequently enhancing the stiffness of the plasma membrane. Oxysterols promoted reactive oxygen species (ROS) generation, THP-1 monocyte attachment and disrupted mitochondrial bioenergetics. We investigated the impact of the liver X receptor (LXR) on oxysterol-induced altered cellular responses, whose activation is known to be associated with repression of inflammation and stabilization of endothelial barrier integrity. Treatment with LXR synthetic agonist dampened oxysterol-induced activation of pro-inflammatory signaling pathways, expression of cytokines and cell adhesion molecules. Additionally, LXR activation protected fpEC from the detrimental effects of oxysterols, including the loss of barrier integrity, the generation of reactive oxygen species (ROS), and the attachment of monocytes. Probucol, a known efflux activity inhibitor of LXR target gene ATP-binding cassette transporter 1 (ABCA1) protein, antagonized the anti-inflammatory effects of LXR agonist against oxysterols. This suggests the potential involvement of ABCA1 in LXR-mediated repression of inflammatory signaling in fpEC. Toll Like Signaling (TLR) 4 inhibition in fpEC abolished oxysterol-induced MAPK and NFκB inflammatory signaling cascade and further downstream responses. Furthermore, inhibition of LXR activation abrogated the vasoprotective effects, suggesting an essential role of LXR in the maintenance of endothelial barrier functions. Collectively, our results indicate that 7-ketoC and 7β-OHC play a role in promoting placental inflammation by triggering the TLR4 signaling pathway and causing endothelial dysfunction, as observed in severe pathophysiological pregnancies. LXR activation has the potential to rescue fpEC from oxysterol-induced inflammation and barrier dysfunction, making them a potential target for the treatment of inflammatory diseases.