Abstract
We recently showed that red blood cells (RBCs) from patients with type 2 diabetes mellitus (T2DM-RBCs) induce endothelial dysfunction through a mechanism involving arginase I and reactive oxygen species. Peroxynitrite is known to activate arginase in endothelial cells. Whether peroxynitrite regulates arginase activity in RBCs, and whether it is involved in the cross-talk between RBCs and the vasculature in T2DM, is unclear and elusive. The present study was designed to test the hypothesis that endothelial dysfunction induced by T2DM-RBCs is driven by peroxynitrite and upregulation of arginase. RBCs were isolated from patients with T2DM and healthy age matched controls. RBCs were co-incubated with aortae isolated from wild type rats for 18 h in the absence and presence of peroxynitrite scavenger FeTTPS. Evaluation of endothelial function in organ chambers by cumulative addition of acetylcholine as well as measurement of RBC and vessel arginase activity was performed. In another set of experiments, RBCs isolated from healthy subjects (Healthy RBCs) were incubated with the peroxynitrite donor SIN-1 with subsequent evaluation of endothelial function and arginase activity. T2DM-RBCs, but not Healthy RBCs, induced impairment in endothelial function, which was fully reversed by scavenging of RBC but not vascular peroxynitrite with FeTPPS. Arginase activity was up-regulated by the peroxynitrite donor SIN-1 in Healthy RBCs, an effect that was inhibited by FeTTPS. Healthy RBCs co-incubated with aortae in the presence of SIN-1 caused impairment of endothelial function, which was inhibited by FeTTPS or the arginase inhibitor ABH. T2DM-RBCs induced up-regulation of vascular arginase, an effect that was fully inhibited by FeTTPS. Collectively, our data indicate that RBCs impair endothelial function in T2DM via an effect that is driven by a peroxynitrite-mediated increase in arginase activity. This mechanism may be targeted in patients with T2DM for improvement in endothelial function.
Highlights
Endothelial dysfunction plays a pivotal role in the development of vascular complications and is one of the early signs of vascular complications in type 2 diabetes mellitus (T2DM)
We were able to demonstrate that red blood cells (RBCs) from patients with T2DM induce endothelial dysfunction, both in arteries isolated from healthy rats and in arteries from non-diabetic patients undergoing coronary artery bypass grafting [3]
Peroxynitrite-Induced glycated hemoglobin were markedly higher in patients with T2DM comparedArginase to healthyActivation controls. in patients with T2DM had higher BMI and triglycerides but lower cholesterol levels compared to the healthy control group (Table 1)
Summary
Endothelial dysfunction plays a pivotal role in the development of vascular complications and is one of the early signs of vascular complications in type 2 diabetes mellitus (T2DM). It is characterized by an imbalance between vasoconstrictors such as enhanced reactive oxygen species (ROS) and vasodilators such as decreased bioavailability of nitric oxide (NO) [1,2]. The underlying causes and pathophysiological changes of the development of endothelial dysfunction in T2DM are complex and. We recently unveiled a previously unknown mechanism underlying cardiovascular dysfunction in T2DM involving red blood cells (RBCs) referred to as erythropathy [3,4,5]. We were able to demonstrate that RBCs from patients with T2DM induce endothelial dysfunction, both in arteries isolated from healthy rats and in arteries from non-diabetic patients undergoing coronary artery bypass grafting [3]
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