BACKGROUND: 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. OBJECTIVES: The authors hypothesized that RBCs from
patients with T2DM induce endothelial dysfunction by up-regulation of arginase. METHODS:
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. RESULTS: 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. CONCLUSIONS: 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.
