Abstract
Nitric oxide (NO) produced by endothelial nitric oxide synthase (NOS) is needed for normal vascular function. During hypertension, diabetes or aging, elevated levels of arginase (ARG) can compete with NOS for available L-arginine thus reducing vascular NO production. Elevated angiotensin II (Ang II) is a key participant of endothelial dysfunction in many cardiovascular diseases and has been linked to elevated ARG activity. In this study we explored the signaling pathway leading to increased ARG expression/activity in responses to Ang II in bovine aortic endothelial cells (BAEC). Treatment of BAEC with Ang II (10 -7 M, 24 hrs) caused a 40±6% increase (p<0.05) in ARG activity. This was accompanied by 30±8% decrease (p<0.05) in NO production. Our studies indicate involvement of p38 mitogen activated protein kinase (MAPK) in Ang II-induced ARG upregulation and reduced NO production as p38 MAPK inhibitor SB202190 (2 μM) prevented the Ang II-induced increase in ARG activity. Our mouse studies also show involvement of p38 MAPK in Ang II-induced vascular dysfunction associated with elevated ARG activity and ARG expression. Ang II (42 µg/kg/h, sc, 2 wks) caused impaired EC-dependent vasorelaxation in mouse aorta (55±7% vs. 75±8% for control). This impairment was prevented by treatment with p38 inhibitor SB203580 (5µg/kg/day). Ang II also caused a 6.2 fold increase in vascular ARG activity/expression that was completely prevented by p38 MAPK inhibition. Additionally, treatment of BAEC with Ang II causes phosphorylation of activating transcription factor-2 (ATF-2) by 10 minutes with a peak at 30 minutes (3.9 fold). Transfection of BAEC with ATF-2 siRNA prevents Ang II-induced increases in ARG activity/expression and maintains NO production. These results indicate that ATF-2 is necessary for enhanced expression of ARG by Ang II. Collectively our results indicate that Ang II increases endothelial ARG activity/expression through a p38 MAPK-ATF-2 pathway leading to reduced NO production and endothelial dysfunction. Targeting these signaling steps might be therapeutic points for preventing vascular endothelial dysfunction associated with elevated ARG activity/expression.
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