Arginase Inhibition Improves Endothelial Function in Patients with Coronary Artery Disease and Type 2 Diabetes
Background—Endothelial dysfunction plays an important role in the early development of atherosclerosis and vascular complications in type 2 diabetes. Increased expression and activity of arginase, metabolizing the nitric oxide (NO) substrate L-arginine, may result in reduced production of NO and thereby endothelial dysfunction. We hypothesized that inhibition of arginase activity improves endothelial function in patients with coronary artery disease (CAD) and type 2 diabetes.
Methods and Results—Three groups of subjects were included: 16 patients with CAD, 16 patients with CAD and type 2 diabetes (CAD+Diabetes) and 16 age-matched healthy control subjects. Forearm endothelium-dependent (EDV) and endothelium-independent (EIDV) vasodilatation were assessed with venous occlusion plethysmography before and during i.a. infusion of the arginase inhibitor Nω-hydroxy-nor-L-arginine (nor-NOHA; 0.1 mg/min). Nor-NOHA was also co-infused with the NO synthase inhibitor (L-NMMA). The expression of arginase was determined in internal mammary artery of patients undergoing bypass surgery. Nor-NOHA markedly increased EDV (up to 2-fold) in patients with CAD+Diabetes and CAD (P < 0.001) but not in the control group. L-NMMA completely inhibited the increase in EDV induced by nor-NOHA. EIDV was slightly improved by nor-NOHA in the CAD+Diabetes group. Arginase I was expressed in vascular smooth muscle cells and endothelial cells, and arginase II was expressed in endothelial cells of patients with and without diabetes.
Conclusions—Arginase inhibition markedly improves endothelial function in patients with CAD and type 2 diabetes suggesting that increased arginase activity is a key factor in the development of endothelial dysfunction.
- Received August 30, 2012.
- Accepted November 2, 2012.
- Copyright © 2012, American Heart Association, Inc. All rights reserved. Unauthorized use prohibited