Erythrocytes From Patients With Type 2 Diabetes Induce Endothelial Dysfunction Via Arginase I

• Published in: Journal of the American College of Cardiology Vol. 72; no. 7; pp. 769 - 780
• Main Authors: Zhou, Zhichao, Mahdi, Ali, Tratsiakovich, Yahor, Zahorán, Szabolcs, Kövamees, Oskar, Nordin, Filip, Uribe Gonzalez, Arturo Eduardo, Alvarsson, Michael, Östenson, Claes-Göran, Andersson, Daniel C, Hedin, Ulf, Hermesz, Edit, Lundberg, Jon O, Yang, Jiangning, Pernow, John
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 14.08.2018; Elsevier Limited
• Subjects: Aged; Animals; Arginase; Arginase - antagonists & inhibitors; Arginase - biosynthesis; Arteries; Bioavailability; Cardiology; Cardiovascular; Cardiovascular disease; Cholesterol; Diabetes; Diabetes mellitus; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2 - blood; Diabetes Mellitus, Type 2 - enzymology; Dose-Response Relationship, Drug; endothelial dysfunction; Endothelium; Endothelium, Vascular - drug effects; Endothelium, Vascular - enzymology; Enzyme Inhibitors - pharmacology; Erythrocytes; Erythrocytes - drug effects; Erythrocytes - enzymology; Female; Humans; Laboratory animals; Low density lipoprotein; Male; Middle Aged; Nitric oxide; Organ Culture Techniques; Patients; Rats; Reactive oxygen species; Reactive Oxygen Species - metabolism; red blood cell; Smooth muscle; Thoracic surgery; Triglycerides; type 2 diabetes; Variance analysis; vascular complication; Vasodilation - drug effects; Vasodilation - physiology; Vasodilator Agents - pharmacology; NADPH; NO; T2DM; eNOS; vascular complication; GK; ABH; T2DM RBC; H2O2; Healthy RBC; endothelial dysfunction; arginase; red blood cell; EIR; NAC; EDR; RBC; type 2 diabetes; NOS; NOX; reactive oxygen species; ROS; KH; EC; red blood cell from patients with type 2 diabetes mellitus; Goto-Kakizaki; 2(S)-amino-6-boronohexanoic acid; Krebs-Henseleit; type 2 diabetes mellitus; endothelial nitric oxide synthase; nitric oxide synthase; endothelium-dependent relaxation; red blood cell from healthy subjects; nitric oxide; endothelial cell; hydrogen peroxide; nicotinamide adenine dinucleotide phosphate; H 2O 2; N -acetyl-cysteine; endothelium-independent relaxation; nicotinamide adenine dinucleotide phosphate oxidase
• ISSN: 0735-1097; 1558-3597; 1558-3597
• DOI: 10.1016/j.jacc.2018.05.052

Cardiovascular complications are major clinical problems in type 2 diabetes mellitus (T2DM). The authors previously demonstrated a crucial role of red blood cells (RBCs) in control of cardiac function through arginase-dependent regulation of nitric oxide export from RBCs. There is alteration of RBC function, as well as an increase in arginase activity, in T2DM. The authors hypothesized that RBCs from patients with T2DM induce endothelial dysfunction by up-regulation of arginase. RBCs were isolated from patients with T2DM and age-matched healthy subjects and were incubated with rat aortas or human internal mammary arteries from nondiabetic patients for vascular reactivity and biochemical studies. Arginase activity and arginase I protein expression were elevated in RBCs from patients with T2DM (T2DM RBCs) through an effect induced by reactive oxygen species (ROS). Co-incubation of arterial segments with T2DM RBCs, but not RBCs from age-matched healthy subjects, significantly impaired endothelial function but not smooth muscle cell function in both healthy rat aortas and human internal mammary arteries. Endothelial dysfunction induced by T2DM RBCs was prevented by inhibition of arginase and ROS both at the RBC and vascular levels. T2DM RBCs induced increased vascular arginase I expression and activity through an ROS-dependent mechanism. This study demonstrates a novel mechanism behind endothelial dysfunction in T2DM that is induced by RBC arginase I and ROS. Targeting arginase I in RBCs may serve as a novel therapeutic tool for the treatment of endothelial dysfunction in T2DM. [Display omitted]