Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Schliefsteiner, C.
Lipoprotein-associated Phospholipase A2 in Placenta and Fetus –
Effect of Obesity and Gestational Diabetes
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Graz Medical University; 2017. pp.
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- Autor*innen der Med Uni Graz:
- Schliefsteiner Carolin
- Betreuer*innen:
- Desoye Gernot
- Marsche Gunther
- Obermayer-Pietsch Barbara
- Wadsack Christian
- Altmetrics:
- Abstract:
- Although diabetes is generally perceived as metabolic disease, it has an additive underlying link to inflammatory mechanisms. Gestational diabetes mellitus (GDM) is defined as any form of diabetes with first on-set and/or recognition during pregnancy. In the past, several studies have shown that GDM causes inflammatory changes in mother and child, and also the placenta – the organ connecting the two. Among these changes are e.g. elevated pro-inflammatory cytokine levels and markers of vascular pathology in maternal and fetal blood, In the placenta, influx of immune cells in GDM has been demonstrated, as well as altered expression of inflammatory, metabolic and anti-oxidative molecules. The study presented here, investigated feto-placental macrophages, so-called Hofbauer cells (HBCs). Human macrophages are very versatile cells and are usually described as either classically activated pro-inflammatory macrophages (M1 polarized) or alternatively activated tissue-remodeling macrophages (M2 polarized). M1 and M2 macrophages can be classified according to their expression of specific cell surface proteins and release of different cytokines. The first part of this study aimed to determine if GDM, being not only a metabolic but also inflammatory condition, could cause alterations in polarization of HBCs. To this extent, HBCs from control and GDM placentas were isolated, and surface proteins were investigated by histochemistry and FACS, cytokine release was measured by ELISA. The results obtained demonstrated that HBCs maintain an M2 polarized phenotype despite presence of GDM, as surface markers and cytokine release were barely changed between control and GDM-HBCs. In the second part of this study, an enzyme produced exclusively by macrophages was investigated. This enzyme, lipoprotein associated phospholipase A2 (LpPLA2), once released from macrophages binds to low density lipoprotein (LDL, 80% in adults) and high density lipoprotein (HDL, 20%) and circulates in blood. It has a unique substrate preference for oxidized phospholipids. It is currently under discussion if LpPLA2 has pro- or anti-inflammatory properties. In pregnancy, elevated maternal LpPLA2 levels have been demonstrated in pre-eclampsia and GDM. Knowledge about LpPLA2 in placenta and fetus is limited, however. Therefore, LpPLA2 activity and regulation in primary HBCs was investigated. It was found that HBCs isolated from GDM placenta released more LpPLA2 activity than controls. LpPLA2 activity was up-regulated in vitro by insulin, leptin, and pro-inflammatory cytokines, but down-regulated by anti-inflammatory cytokines. Furthermore, as LpPLA2 circulates associated to lipoproteins, fetal lipoproteins from cord blood of healthy and GDM fetuses were isolated and investigated for LpPLA2 activity and distribution among lipoproteins. HDL was identified as major carrier of LpPLA2 in the fetus, which is in contrast to adults. Also, HDL-LpPLA2 was significantly increased in GDM and positively correlated with maternal BMI. A mixture of oxidized phospholipids as well as a specific inhibitor of LpPLA2 activity were employed to conduct functional assays on placental endothelial cells with native HDL and HDL with inactivated LpPLA2. These results demonstrated that HDL-LpPLA2 in placenta and fetus might exert anti-oxidative and vasculo-protective actions.