Rodford, Joanne, Li, Francois Y., Siow, Richard C.M., Hanson, Mark A., Mann, Giovanni E. and Clough, Geraldine F.
In utero protein restriction leads to a down-regulation of antioxidant gene expression in adult male offspring
Proceedings of the Physiological Society
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In rats, restriction of dietary protein during pregnancy leads to raised blood pressure, impaired vasodilatation (Brawley et al. 2003) and increased oxidative damage (increased protein carbonyl concentration) (Langley-Evans et al. 2005) in the male offspring. The aim of the present study was to assess mRNA expression of three key endothelial antioxidant genes, heme oxygenase-1 (HO-1), glutamate cysteine ligase (GCL) and manganese superoxide dismutase (Mn-SOD), as well as, endothelial nitric oxide synthase (eNOS), in the liver and mesenteric arteries of adult male offspring of protein-restricted rat dams. Pregnant Wistar rats (240 g) were fed either a control diet (C; 18% casein, n = 6) or a protein-restricted diet (PR; 9% casein, n = 6) throughout gestation from conception. At 120 days of age, male offspring were culled and liver and small mesenteric arteries (~250 µm diameter and ~12 arteries per animal) were removed and snap frozen in liquid nitrogen. RNA was extracted and mRNA levels of HO-1, GCL, MnSOD and eNOS were measured using quantitative real-time PCR and normalised with respect to 28S RNA (Mahn et al. 2005). Data are presented as mean ± SEM, and differences assessed by two-way analysis of variance (ANOVA) with significance accepted at p<0.05. The mRNA expression of all three antioxidant genes was reduced in the livers of the PR compared to C male offspring (HO-1: C; 1807 ± 439, n = 11, PR; 424 ± 109, n = 11, p = 0.006, GCL: C; 120 ± 16, n = 11, PR; 70 ± 11, n = 11, p = 0.016, MnSOD: C; 1544 ± 189, n = 11, PR; 1044 ± 101, n = 12, p = 0.027, figures expressed as gene mRNA relative to 28s RNA). Expression in the mesenteric arteries followed the same trend, being reduced by 14% for HO-1, 36% for MnSOD and 36% for GCL but did not reach significance for any of the three genes. The eNOS mRNA expression was not significantly different between the two groups in either tissue type. These findings demonstrate that the previously observed oxidative damage in the offspring of in utero protein-restricted rats (Langley-Evans et al. 2005) may be in part due to a reduced antioxidant enzyme defence. Diminished antioxidant defences may also account for the previously observed vascular dysfunction in the mesenteric arteries due to a nitric oxide–reactive oxygen species imbalance in the PR offspring.
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