Diabetes Enhances Arginase activity/expression and Vascular Endothelial dysfunction via ERK and p38 MAPK Activation

Mitogen-Activated Protein Kinase (MAPK) and enhanced arginase activity both have been implicated in vascular endothelial dysfunction (VED). We recently reported involvement of the RhoA/Rho kinase (ROCK) pathway in the activation of arginase in endothelial cells treated with high glucose (HG) via a ROCK inhibitor. We also demonstrated that activation of arginase in aorta and in corpora cavernosa of angiotensin II-treated mice involves p38 MAPK activation. However, the signaling mechanisms involved with arginase activation in diabetes remains largely unknown. We propose to define regulators downstream from the ROCK pathway that lead to arginase activation. In this proposal, we hypothesize that following diabetes-induced the RhoA/Rho kinase (ROCK) activation, Extracellular Signal-Regulated Kinase (ERK1/2) and p38 MAPK are activated, which leads to increased arginase activity and arginase I expression. This occurs via subsequent phosphorylation and activation of transcription factors that leads to increased gene expression and enzyme activity. Our preliminary results showed that aorta of streptozotocin (STZ)-induced diabetic mice and high glucose (HG, 25 mM) incubation in isolated aorta from non-diabetic mice (24 hrs) and in bovine aortic endothelial cells (BAEC, 72 hrs) impaired endothelium-dependent vasorelaxation and increased arginase activity and arginase I expression in vascular tissues and in endothelial cells. Treatment with inhibitors of ERK (PD98059, 10 µM), p38 MAPK (SB203580, 10 µM), ROCK (Y-27632, 1 µM) or with arginase inhibitor (BEC, 100 µM) blunted these effects. These preliminary findings indicate that increased arginase activity and arginase I expression occur in diabetes/HG treatment via the ERK and p38 MAPK pathways and contribute to VED. We predict that activation of transcription factors is positively regulated by MAPKs, and arginase activity is caused by an increase in arginase expression through activation of transcription factor or associated with arginase promoter region. (AHA Program: Postdoctoral Fellowship)