Red blood cells (RBCs) induce endothelial dysfunction in type 2 diabetes (T2D), but the mechanism by which RBCs communicate with the endothelium is unknown. This study tested the hypothesis that extracellular vesicles (EVs) secreted by RBCs act as mediators of endothelial dysfunction in T2D. Despite a lower production of EVs derived from RBCs of T2D patients (T2D RBC-EVs), their uptake by endothelial cells was greater than that of EVs derived from RBCs of healthy individuals (H RBC-EVs). T2D RBC-EVs impaired endothelium-dependent relaxation, and this effect was attenuated following inhibition of arginase in EVs. Inhibition of vascular arginase or oxidative stress also attenuated endothelial dysfunction induced by T2D RBC-EVs. Arginase-1 was detected in RBC-derived EVs, and arginase-1 and oxidative stress were increased in endothelial cells following coincubation with T2D RBC-EVs. T2D RBC-EVs also increased arginase-1 protein in endothelial cells following mRNA silencing and in the endothelium of aortas from endothelial cell arginase-1–knockout mice. It is concluded that T2D-RBCs induce endothelial dysfunction through increased uptake of EVs that transfer arginase-1 from RBCs to the endothelium to induce oxidative stress and endothelial dysfunction. These results shed important light on the mechanism underlying endothelial dysfunction mediated by RBCs in T2D.

Red blood cells from patients with STEMI and systemic inflammation induce endothelial dysfunction ex vivo. The RBC-induced endothelial dysfunction is mediated through increased arginase 1 and a shift in the redox balance toward oxidative stress. Inhibition of arginase or free radicals attenuates the impairment of endothelial function. The study suggests that red blood cells deserve attention as a key player in systemic inflammation and STEMI.

MicroRNAs are valuable biomarkers in cardiometabolic disease, but heparinized tubes hinder their detection because of qPCR interference. RBCs, which express abundant microRNAs like miR-210-3p, may serve as an alternative. microRNAs, including miR-210-3p, are consistently detectable in RBCs at comparable levels between heparinized and EDTA tubes. miR-210-3p levels in RBCs are similarly reduced in heparinized tubes of patients with type 2 diabetes. Thus, RBCs offer a promising solution for miRNA biomarker studies, overcoming heparin-related challenges.

Background: Arginase influences cardiac tolerance to ischemia–reperfusion by modulating nitric oxide (NO) signaling. In type 2 diabetes (T2D), elevated arginase activity may worsen ischemic injury through red blood cells (RBCs), but the specific roles of arginase isoforms are unclear. Methods: C57BL/6 and db/db mice were pretreated with ARG1 or ARG2 antisense oligonucleotides (ASO) for six weeks. Conditional ARG1 knockout (ARG1^fl/fl/Tie2Cre^tg/−) and wild-type littermates were also studied. Mice underwent coronary artery ligation and reperfusion in vivo for infarct size assessment. In ex vivo experiments, buffer-perfused hearts were subjected to global ischemia–reperfusion with or without RBCs to evaluate recovery of left ventricular developed pressure (LVDP). Results: ARG1 knockdown, but not ARG2, improved post-ischemic recovery of LVDP in isolated hearts. RBCs from ARG1 ASO-treated mice enhanced recovery in wild-type hearts, while ARG1 knockout reduced infarct size compared with controls. Cardioprotection was abolished by NO synthase inhibition. RBCs from male and female ARG1 knockout mice improved LVDP recovery compared with RBCs from wild-type mice. In T2D mice, impaired recovery was restored by ARG1 ASO or RBCs from ARG1 ASO-treated T2D mice. Conclusions: Arginase 1, but not arginase 2, limits cardiac tolerance to ischemia–reperfusion and contributes to increased vulnerability in T2D.