Arginase inhibition prevents vascular endothelial dysfunction in a type 2 diabetes model (1139.13)

Abstract

Type 2 diabetes is associated with increased levels of reactive oxygen species (ROS) and activation of blood monocytes. Both conditions significantly increase risk of cardiovascular disease, with vascular endothelial dysfunction (VED) recognized as a key event. We previously reported that increased vascular arginase activity (AA) is associated with VED in type 1 diabetic mice. Arginase 1 knockdown or arginase inhibitor (2(S)‐amino‐6‐boronohexanoic acid, ABH) treatment can prevent these effects. We hypothesized that ABH treatment would prevent VED in Type 2 diabetic (db/db obese) mice. To test this, plasma and aorta were collected from 18 wk old lean control (LC) and db/db mice or db/db mice treated with ABH (8 mg/kg/day, drinking water, last 7 weeks). The AA was increased 6.7 fold in plasma and 4.4 fold in aorta of db/db mice vs LC. ABH treatment blocked these increases. The db/db mice exhibited a decrease in maximum vasorelaxation to acetylcholine to 53% vs 76% for LC and a 2.1 fold increase in numbers of circulating, activated monocytes. Both effects were blocked by ABH. Plasma ROS (lipid peroxides) were elevated 2.5 fold in db/db mice and were not altered by ABH treatment. In conclusion, systemic inhibition of arginase prevents type 2 diabetes‐induced VED and blocks the increase in activated monocytes, without altering plasma ROS levels.