Enhanced sensitivity to 4-hydroxynonenal and impaired redox signaling in human endothelial cells in gestational diabetes

Abstract

Fetal exposure to gestational diabetes (GDM) in utero is strongly associated with a higher risk of cardiovascular disease and insulin resistance in later life, and accumulating evidence suggests this may be a consequence of fetal programming potentially involving epigenetic influences.1 Notably, offspring of mothers with GDM exhibit elevated blood pressure and reduced endothelium-dependent reactivity. We previously reported abnormal nitric oxide production, insulin resistance and reduced cell proliferation in fetal umbilical vein endothelial cells (HUVEC) from GDM pregnancies,2,3 and in parallel studies with endothelial cells from pre-eclamptic pregnancies, associated with in utero oxidative stress, identified abnormalities in NO production and regulation of [Ca2+]i.4,5 These phenotypic changes are maintained during culture, highlighting the involvement of fetal programming and epigenetics. As placental oxidative stress is propagated to the maternal and fetal vasculature via circulating lipid peroxides and H2O2 in GDM, we hypothesised that sustained oxidative stress in the fetal vasculature in utero may impair endogenous antioxidant defences. We established that activation of the redox sensitive transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2)6 and its downstream target antioxidant enzymes is markedly inhibited in HUVEC from GDM pregnancies. Fetal endothelial cells exhibited marked deficits in glutathione synthesis, increased basal mitochondrial superoxide production, reduced nuclear translocation of Nrf2, and diminished adaptive increases in the expression of the Nrf2 target genes heme oxygenase-1 (HO-1) and/or NAD(P)H quinone oxidoreductase 1 (NQO1) in response to the lipid peroxidation product 4-hydroxynonenal (4-HNE). A proteomic analysis of normal and GDM HUVEC confirmed the altered GDM phenotype, characterised by markers of increased oxidative stress, reduced antioxidant protection and reduced cell proliferation.7 More recently, we have confirmed increased 4-HNE induced damage and attenuated Nrf2-regulated gene expression in umbilical artery smooth muscle cells from GDM mothers. The altered phenotype of fetal venous endothelial and arterial smooth muscle cells derived from GDM pregnancies may underlie an increased risk of developing type 2 diabetes and cardiovascular disease in childhood and early adulthood.8-12