High glucose limits NO production through ATF‐2 and c‐Jun transcriptional regulation of Arginase

Abstract

Vascular endothelial dysfunction (VED) is characterized by impaired endothelial cell (EC) production or availability of nitric oxide (NO). NO produced by endothelial NO synthase (NOS) is needed for normal vascular function. During diabetes or hypertension, elevated levels of arginase (ARG) can compete with NOS for available arginine thus reducing vascular NO. Diabetes has been linked to elevated ARG and associated with VED. In this study we explored transcriptional regulation of increased ARG expression/activity in response to high glucose (HG) in EC. Previously we showed involvement of activating transcription factor‐2 (ATF‐2) in upregulating ARG I in response to angiotensin II (Ang II). Treatment of EC with HG (25 mM, 72 hrs) caused an increase in ARG activity, accompanied by decrease in NO production. Depletion of ATF‐2 or c‐Jun by siRNAs prevented both of the effects of HG. Also, HG enhanced ARG I gene transcriptional activity measured as luciferase activity in ECs transfected with ARG I promotor luciferase. Transfection of EC with ATF‐2 or c‐Jun siRNA prevented this increase in luciferase activity indicating that ATF‐2 and c‐Jun are necessary for enhanced expression of ARG I under HG conditions. These and our earlier data indicate that HG and Ang II signal through a common pathway to induce ARG and limit NO. These signaling steps might be therapeutic targets for preventing VED associated with elevated ARG levels.