Abstract 20890: Ddah1 Protects From Angiotensin II-Induced Development of Hypertension and Vascular Remodeling

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Abstract

Angiotensin II-dependent development of hypertension and vascular remodeling are mediated via endothelial dysfunction. The latter is mediated via ANGII-induced threonine (Thr) phosphorylation of the protein kinase AKT. Dimethylarginine dimethylaminohydrolase 1 (DDAH1) is a cytoplasmic protein, which has been shown to prevent Thr phosphorylation of AKT. We tested the hypothesis that DDAH1 prevents ANGII-dependent development of hypertension and vascular remodeling. DDAH1 transgenic (TG) and wild type (WT) littermate mice were infused with moderate (0.75 mg/kg/day) and high (1.5 mg/kg/day) doses of ANGII for 4 weeks using osmotic minipumps. Systolic blood pressure (SBP) was measured using the tail cuff method. Endothelial function was assessed in isolated aortic rings. Structural changes in aortic wall were assessed by histological analysis. SBP was not different between TG and WT mice before ANGII infusion and at the 1st week of infusion, however, TG mice had significantly lower (P<0.01) SBP compared to WT littermates at weeks 2, 3 and 4. Assessment of endothelial function with acetylcholine showed better endothelium-dependent aortic relaxation in TG mice. Histological assessments revealed less (P<0.01) of aortic hypertrophy and fibrosis in TG compared to WT mice. Significantly (P<0.01) more elastin was preserved in TG mice. Matrix metalloproteinase 2 (MMP2) activity was significantly (P<0.01) lower in aortas of TG than of WT mice. Flow cytometry revealed that aortic infiltration of CD45+, CD3+, CD8+ and CD4+ T-cells was significantly lower (P<0.01) in TG than in WT mice. These beneficial effects were seen after 4 weeks of ANG II infusion with the moderate dose and after 2 weeks of ANGII infusion with the high dose. Our study conclusively demonstrates that overexpression of DDAH1 antagonizes ANGII-dependent development of hypertension and vascular remodeling. The effect is dependent on the ANGII dose, resulting in a complete prevention at a moderate ANGII dose and temporal delay at a high ANGII dose.

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