Abstract 494: Loss of Gstm1 Alters Blood Pressure Homeostasis and Augments Angiotensin II-induced Hypertension
GSTM1 gene encodes an enzyme that belongs to a superfamily of Glutathione-S-transferases that metabolize xenobiotic, and a broad range of reactive oxygen species and electrophilic compounds formed as secondary metabolites during the oxidative stress. There is a general consensus that oxidative stress contributes to development of hypertension (HTN). We hypothesized that Gstm1 may influence blood pressure (BP) regulation through its central role in modulating redox homeostasis. Therefore the objective of this study was to determine the response of Gstm1 knockout (KO) mice to 2 models of hypertension that are mediated in part by oxidative stress: 1) high salt model, and 2) angiotensin II model.
Methods: Gstm1-/- (KO) mice were generated on the 129S6 background through conventional gene targeting strategy. Hypertension was induced using high salt diet (HSD, 6% NaCl) for 2 weeks or by infusion of angiotensin II (Ang II) via mini-osmotic pump at dose 1000 ng/kg/min for 3 weeks. Systolic BP (SBP) at baseline and under high salt condition was measured using radio-telemetry. Tail-cuff manometry was used to measure SBP in Ang II induced hypertension. Urinary isoprostane (index of oxidative stress) was measured using ELISA assay. For all studies, n ≥ 4 per group.
Results: By radiotelemetry, Gstm1 KO mice display a modest but significantly higher baseline SBP compared to their wild type (WT) littermates: KO: 138.8 ± 1.3; WT: 132.1 ± 1.1, p < 0.01. On high salt diet, both WT and KO mice displayed salt sensitivity, and the difference in SBP was maintained between the two genotypes (KO: 148.7 ± 1.6; WT: 143.8 ± 1.3, p < 0.05). Urinary isoprostane (ng/100 mg of body weight) is significantly higher in KO mice than WT mice at baseline as well as during HSD (baseline: KO 15.1 ± 2.9; WT: 8.0 ± 0.8, p < 0.04; HSD: KO 27.2 ± 2.0; WT: 21.0 ± 1.3, p = 0.04). Angiotensin II infusion augments the difference in SBP between WT and KO mice (185.0 ± 3.1; WT mice 175.4 ± 1.4, p < 0.05).
Conclusion: Loss of Gstm1 results in elevated baseline blood pressure and augmented Ang II induced hypertension. The altered blood pressure homeostasis from deficiency in GSTM1 enzyme may be mediated by a decreased capacity to handle oxidative stress.
- © 2013 by American Heart Association, Inc.