Angiotensin II‐induced elevation of arginase activity and impaired vasorelaxation can be prevented by p38 MAPK inhibition

Enhanced vascular arginase (ARG) activity impairs endothelial dependent vasorelaxation by decreasing L‐arginine availability to endothelial nitric oxide (NO) synthase, thereby reducing NO production. Elevated angiotensin II (Ang II) is a key component of endothelial dysfunction (ED) in many cardiovascular diseases and has been linked to elevated ARG activity. We have shown previously that Ang II elevates ARG activity and reduces NO formation in endothelial cells (EC) through RhoA and p38 mitogen activated protein kinase (MAPK) pathways. Here we investigated the effects of inhibiting p38 MAPK on Ang II‐induced vascular ED and increased ARG activity in vivo compared to inhibition of ARG or the use of ARG knockout (KO) mice. In wild type mice given s.c. infusion of Ang II (42 μg/kg/h, 2 wks), vascular ARG activity was elevated compared to controls and was accompanied by impaired EC‐dependent vasorelaxation. Treatment with the p38 MAPK inhibitor SB 203580 (5 μg/kg/d, s.c.) or ARG inhibitor ABH (8 mg/kg/d, po) significantly inhibited the Ang II‐induced increase in ARG activity and improved vasorelaxation. In ARG KO mice, Ang II treatment failed to cause ED. Collectively, our results indicate involvement of p38 MAPK in the Ang II signaling pathway for ARG elevation and ED. Inhibiting p38 MAPK might be a beneficial therapeutic target for ED associated with Ang II. Support: AHA 10PRE4440000, NIH HL70215 & EY11766NHLBI.