Abstract 378: Red Blood Cells From Patients With Type 2 Diabetes Induce Endothelial Dysfunction Through Up-Regulation of Arginase I

Abstract

We previously showed that increased arginase activity is a key mechanism for endothelial dysfunction in patients with type 2 diabetes mellitus (T2DM) thereby arginase inhibition improves endothelial function. Recently, we demonstrated a crucial role of red blood cells (RBCs) in control of cardiac function via an arginase-dependent regulation of nitric oxide export from RBCs, suggesting a direct interaction of RBCs with cardiovascular function. Considering an increase in arginase activity in T2DM, we hypothesized that RBCs induce endothelial dysfunction in T2DM via up-regulated arginase I. Healthy rat aortas were incubated with RBCs from patients with T2DM (T2DM-RBCs) and age-matched healthy subjects (H-RBCs) for 18 h in the absence and presence of the arginase inhibition or scavenging of reactive oxygen/nitrogen species (ROS/RNS). Following the incubation, endothelium-dependent and -independent relaxations (EDR and EIR) were determined using wire myograph. Human internal mammary arteries (IMAs) obtained from non-diabetic patients who underwent cardiac surgery were also incubated with RBCs for functional evaluation. Arginase activity and protein expression were determined in RBCs. EDR was impaired in vessels incubated with T2DM-RBCs (Emax: 43.2±3.0% in aortas, n=8; 32.3±2.7% in IMAs, n=3) but not H-RBCs (Emax: 74.3±3.4% in aortas; 71.5±5.1% in IMAs) in comparison with buffer (Emax: 74.4±2.3% in aortas; 73.1±5.0% in IMAs; P<0.01 vs. T2DM-RBCs). EIR was not affected by T2DM-RBCs. The impairment in EDR in rat aortas was fully reversed by inhibition of arginase, ROS and RNS in RBCs. Arginase activity was significantly elevated in T2DM-RBCs. The increased arginase activity was attributed to arginase I, as there was increased arginase I expression in RBCs, whereas no arginase II expression was detected. Moreover, high glucose and RNS stimulation increased arginase activity in H-RBCs, while ROS/RNS scavenging decreased arginase activity in T2DM-RBCs. This study demonstrates a novel mechanism behind endothelial dysfunction that T2DM-RBCs induce endothelial dysfunction via ROS/RNS-dependent up-regulation of arginase I. Targeting arginase I in RBCs may serve as a novel therapeutic tool for treatment of endothelial dysfunction in T2DM.