Arginase inhibition improves vascular function and restores NO production in diabetic conditions

Abstract

Cardiovascular complications of diabetes are a leading cause of morbidity and mortality. Vascular endothelial dysfunction (VED) is strongly implicated in the pathogenesis of diabetic vascular complications. Diabetes has been linked to elevated arginase and associated with vascular endothelial dysfunction. The pathological process is characterized by impaired endothelial cell production of nitric oxide (NO) and/or decreased NO bioavailability. NO is produced by activity of endothelial NO synthase (eNOS) on its substrate L‐arginine. Arginase in ECs also uses L‐arginine as a substrate to produce urea and ornithine. Thus, elevated levels of arginase will limit availability of L‐arginine to eNOS and decrease NO production.We performed analysis of arginase activity in type 2 diabetes mellitus (T2DM). Arginase activity was elevated in diabetes patients as compared to age‐matched healthy volunteers. Levels of arginase activity had a positive correlation with HbA1c levels in diabetic patients (R2=0.8 Pearson r=0.87). Cell studies also agreed with these findings, as high glucose (25 mmol/L, 72 hrs) treatment to ECs resulted in a significant increase in arginase activity. This increase in arginase activity was concomitant with a 27% drop in NO produced by EC. Inhibition of arginase by ABH (100 uM) restored NO level to normal.The effects of L‐citrulline, a natural arginase inhibitor, on inhibiting arginase activity in T2DM patients was assessed. Twenty five patients received L‐citrulline supplements (2000 mg/day) for 1 month. Arginase activity was decreased 30% in T2DM patients after taking L‐citrulline supplements. There was a modest improvement on HbA1c levels in these patients. The effect on L‐citrulline on arginase activity was also measured in BAECs grown in high glucose conditions. L‐citrulline 100μM completely prevented the increase in arginase activity and restored NO production levels. These data indicate that inhibiting arginase activity can have therapeutic benefits in diabetic patients by preventing vascular dysfunction and maintaining NO levels.Our results indicate that arginase can be regarded as a novel marker for the vascular complications of diabetes. Drugs targeting arginase or its signaling pathway may show benefits in delaying or preventing these vascular complications.Support or Funding InformationThe University of Jordan deanship of researchThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.