Diabetes/High Glucose‐Induced Enhancement of Arginase and Endothelial Dysfunction involves Extracellular Signal‐Regulated Kinases (ERK) and p38 Mitogen‐Activated Protein Kinases (MAPK)

MAPK and enhanced arginase (ARG) activity both have been implicated in vascular endothelial dysfunction (VED). We recently reported that activation of ARG in angiotensin II‐treated mice involves p38 MAPK activation. Here we tested the hypothesis that streptozotocin diabetic mice and high glucose (HG)‐treated bovine aortic endothelial cells (BAEC) or aorta have increased ARG activity/expression via activation of ERK and p38 MAPK pathways which contributes to VED. Our studies showed that diabetes or exposure of BAEC (72 hr) or non‐diabetic aorta (24 hr) to HG (25 mM) increase ARG activity and ARG‐I expression. Treatment with inhibitors of ERK (PD98059, 10 μM), p38 MAPK (SB203580, 10 μM) or with ARG inhibitor (BEC, 100 μM) blunted these effects. Additionally, Rho kinase inhibitor (Y‐27632, 1 μM) also prevented HG‐stimulated ARG activity in BAEC and aorta. Activated phosphorylated ERK and p38 MAPK were observed prior to ARG activation in HG‐treated BAEC or aorta. Furthermore, endothelium‐dependent NO‐mediated vasorelaxation to acetylcholine was significantly reduced in diabetes or HG‐treated aorta compared with control mice or normal glucose aorta (5 mM). This impairment was largely prevented by inhibition of ERK, p38 MAPK, Rho‐kinase or ARG. These findings indicate that increased ARG activity/expression occurs in diabetes/HG treatment via the ERK and p38 MAPK pathways and contributes to VED.