Proceedings of The Physiological Society
University of Oxford (2011) Proc Physiol Soc 23, C8
Gestational diabetes impairs Nrf2/ARE mediated redox signalling in fetal endothelial cells: implications for developmental priming of endothelial dysfunction in offspring
X. Cheng1, R. Siow1, X. Yin1, M. Mayr1, G. E. Mann1
1. Cardiovascular Division, King's College London, London, United Kingdom.
Gestational diabetes (GDM) affects ~7% pregnancies worldwide (Buchanan & Xiang, 2005), and offspring from gestational diabetic mothers are predisposed to type 2 diabetes and cardiovascular diseases in adulthood (Cheng et al., 2011). We previously reported abnormal NO production and reduced cell proliferation in foetal umbilical vein endothelial cells (HUVEC) cultured from GDM pregnancies (Sobrevia et al., 1995; Mann et al., 2003). HUVEC from normal and diabetic pregnancies were cultured in 20% serum M199 and then treated with the lipid peroxidation product 4-hydroxynonenal (HNE, 20µM) for 3-24h. In the present study, HNE induced adaptive increases in intracellular glutathione were diminished in GDM cells (GDM: 73 ± 5 vs normal: 112 ± 9 nmol/mg, mean ± S.E.M., n=5-7, p<0.01, Student’s t-test) and basal mitochondrial reactive oxygen species generation was elevated. HNE induced activation of the redox sensitive transcription factor NF-E2 related factor 2 (Nrf2) was impaired in GDM HUVEC, as evidenced by decreased mRNA expression of the glutamate/cystine transporter (xCT) and the phase II defence enzyme NAD(P)H quinone oxidoreductase 1 (NQO1). HNE induced DNA fragmentation was also increased in GDM compared to normal HUVEC, consistent with decreased endogenous antioxidant defences in GDM cells. A proteomic analysis further confirmed the altered phenotype of GDM HUVEC, characterised by markers of increased oxidative stress, reduced antioxidant protection and reduced proliferation. This altered vascular phenotype may contribute to an increased risk of type 2 diabetes and cardiovascular disease in the offspring of gestational diabetic mothers in later life.
Where applicable, experiments conform with Society ethical requirements