Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Sreckovic, I.
Functionality of fetal high-density lipoprotein particles: Heterogeneity and relationship to Gestation Diabetes Mellitus
[ Dissertation ] Medical University of Graz; 2013. pp. 103
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- Autor*innen der Med Uni Graz:
- Sreckovic Ivana
- Wadsack Christian
- Betreuer*innen:
- Frank Sasa
- Olschewski Andrea
- Wadsack Christian
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- Abstract:
- The human high-density lipoprotein (HDL) represents the major cholesterol carrying lipoprotein class in cord blood, while cholesterol is mainly carried by low-density lipoprotein in maternal serum. Changes in maternal lipid metabolism and cholesterol supply might also affect fetal outcome with consequences later in life. Gestational Diabetes Mellitus (GDM), most common complication of pregnancy, is related to postnatal fetal obesity and to higher risk for vascular events. We tested the hypothesis that fetal HDL (fHDL) carries proteins qualitatively and quantitatively different from maternal HDL (mHDL) and that GDM could cause alterations of fHDL proteome and probably its biological function. Shotgun proteomics and biochemical analyses were used to assess composition/function of fHDL and mHDL isolated from uncomplicated and GDM human pregnancies at term of gestation. The pattern of analyzed proteins that were statistically elevated in fHDL (apoE, proteins involved in coagulation, transport processes) suggests a particle characteristic for the light HDL2 sub-fraction. In contrast, proteins that were enriched in mHDL (apoL, apoF, PON1, apoD) have been described almost exclusively in the dense HDL3 fraction and relevant to its anti-oxidative function and role in innate immunity. Strikingly, PON1 mass and activity were 5-fold lower (p<0.01) in the fetus, which was accompanied by attenuation of anti-oxidant capacity of fHDL. Despite almost equal quantity of CETP in maternal and fetal plasma, its enzymatic activity was 55% lower (p<0.001) in the fetal circulation, whereas LCAT activity was not altered. When comparing control and GDM HDL eight proteins involved in lipid metabolism, inflammation and innate immunity were differentially expressed. Among them apoM, PON1, prothrombin (decreased, p<0.05) and SAA1 (increased, p<0.05) showed the same differences on both, mGDM HDL and fGDM HDL. The lower PON1 protein expression was corroborated by lower activity (p<0.05) which was accompanied by attenuation of anti-oxidant capacity of GDM HDL. GDM caused enrichment of HDL with triglycerides followed by decreased HDL-cholesterol levels (p<0.05). Disturbances observed in GDM HDL lipid moiety might be caused by CETP mass and activity alterations. Rate of free cholesterol efflux from trophoblasts to maternal and from placental endothelial cells to fGDM HDL was diminished (p<0.05). With the discovery of apoM as an important carrier of S1P in HDL particles and due to the similar apoM levels in mHDL and fHDL, it is comprehensible that fHDL is also the carrier of sphingosine-1-phosphate (S1P). FHDL-apoM-S1P complex is powerful chemoattractant and induced migration of human placental arterial endothelial cells (HPAEC). Secondly, S1P associated to fHDL interaction with S1P receptor (S1PR) on HPAEC and triggered rearrangement of actin fibers and formation of prominent cortical actomyosin ring which further leads to increment of barrier integrity. By blocking S1PR1 and S1PR3 with selective antagonist effect of HDL-S1P were abolished (p<0.001). Notably, in GDM 46% less S1P is associated to fHDL (p<0.01) which caused that fGDM HDL functions to induce barrier integrity and migration of HPAEC were diminished (p<0.001). These findings indicate that maternally-derived HDL differs from fHDL with respect to its proteome, size and function. Absence of apoA-1, apoL and PON1 on fHDL is associated with decreased anti-oxidative properties together with deficiency in innate immunity collectively indicating distinguish HDLs in fetuses. Alterations occurring in HDL composition and metabolism to GDM are intimately associated with impaired anti-oxidative and vasoprotective properties of this particle.