Elucidating the role of novel angiogenesis-related proteins, FKBPL and SIRT-1, in trophoblast cells exposed to diabetic stimuli: potential implications for preeclampsia
- Publisher:
- Springer Science and Business Media LLC
- Publication Type:
- Conference Proceeding
- Citation:
- Diabetologia, 2017, 60, (Suppl 1), pp. 1-608
- Issue Date:
- 2017-09
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| 53 suprdsup EASD Annual Meeting of the European Association for the Study of Diabetes Lisbon, Portugal, 11 - 15 September 2.pdf | 49.42 MB |
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Background and aims: Diabetic vascular complications are closely related to irregular angiogenesis, oxidative stress and lipid peroxidation.
Preeclampsia (PE) is a pregnancy condition characterised by high blood
pressure, proteinuria and multi-organ dysfunction. PE occurs in 4-6% of
pregnancies; however in women with diabetes the incidence of PE is
increased four-fold. Furthermore, PE does not only have short-term risks,
but long-term is associated with cardiovascular disease and/or Type 2
diabetes in both mothers and offspring. Despite research efforts in this
area, currently there are no reliable early biomarkers, preventative or
treatment strategies for PE, other than delivery. Moreover, paucity of
mechanistic data is impeding the development of successful preventativeand curative therapies of PE, particularly in the context of diabetes. The novel angiogenesis-related protein, FKBPL, is a critical regulator of developmental and pathological angiogenesis and closely associated with nutrient-sensing protein, SIRT-1. Therefore, FKBPL may play a key role in the pathophysiology of PE associated with diabetes.
Materials and methods: Three different trophoblast cells lines
(HTR8.SV.neo, BeWo and Jar) were exposed to diabetic stimuli: normal
vs. high glucose (5.5 vs. 10, 20, 40 mM), native vs. highly oxidised,
glycated low density lipoprotein (N- vs. HOG-LDL; 25 μg protein/ml),
or hypoxia (1%); then FKBPL and SIRT-1 protein expression and mRNA
levels were measured in cell lysates. FKBPL and SIRT-1 were also measured in placental extracts using western blotting.
Results: FKBPL and SIRT-1 protein expression differed across the three
trophoblast cell lines, with Jar cells expressing the highest levels of
FKBPL and SIRT-1, BeWo cells expressing the lowest level of SIRT-1
and HTR8.SV.neo cells expressing the lowest level of FKBPL. In BeWo
cells treated with high vs. normal glucose (48 h), FKBPL mRNA levels
were increased 1.3-fold (10mM; p=0.001; n=3), 1.21-fold (20mM;
p=0.03; n=3) and 1.46-fold (40mM; p=0.007; n=3). In HTR8.SV.neo
cells treated with HOG-LDL (24 h) a 2-fold increase of FKBPL protein
was demonstrated compared to native LDL (p=0.048; n=4). No significant changes in FKBPL or SIRT-1 protein expression were observed in
Jar cells treated with HOG-LDL, perhaps because of higher FKBPL
protein expression in Jar vs. HTR8.SV.neo (p=0.03; n=3). Exposure of
HTR8.SV.neo cells to hypoxia (1%) led to 2.4- and 3.8-fold reductions in
FKBPL (p=0.003; n=3) and SIRT-1 (p=0.02; n=3) protein expressions,
respectively. In concert, we have previously published that endothelial
cells (HMEC-1) exposed to hypoxia (0.1%) exhibited reduced FKBPL
secretion. FKBPL is also strongly expressed in placental extracts.
Conclusion: Our data suggest that FKBPL and SIRT-1 may have important regulatory and biomarker roles in the development of PE as a vascular complication of diabetes. Pregnancies complicated by both diabetes
and PE might exhibit elevated levels of FKBPL/SIRT-1 in early gestation
(hyperglycaemia, oxidative stress) and reduced levels in late gestation
(placental hypoxia). We plan to investigate this in longitudinal plasma
samples from patients with and without diabetes, and with and without
PE.
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