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.

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Extracellular vesicles (EVs), including exosomes, microvesicles and apoptotic bodies, have recently received attention as essential mechanisms for cell‐to‐cell communication in cardiovascular disease. EVs can be released from different types of cells, including endothelial cells, smooth muscle cells, cardiac cells, fibroblasts, platelets, adipocytes, immune cells and stem cells. Non‐coding (nc)RNAs as EV cargos have recently been investigated in the cardiovascular system. Up‐ or downregulated ncRNAs in EVs have been shown to play a crucial role in various cardiovascular diseases. Communication via EV‐derived ncRNAs can occur between cells of the same type and between different types of cells involved in the pathophysiology of cardiovascular disease. In the present review, we highlight the important aspects of diverse cell‐derived EVs and their ncRNA cargos as disease mediators and potential therapeutic targets in atherosclerosis, coronary artery disease, ischaemic heart disease and cardiac fibrosis. In addition, we summarize the potential of EV‐derived ncRNAs in the treatment of cardiovascular disease. Finally, we discuss the different methods for EV isolation and characterization. A better understanding of the specific role of EVs and their ncRNA cargos in the regulation of cardiovascular (dys)function will be of importance for the development of diagnostic and therapeutic tools for cardiovascular disease. image