Long Duration of Type 2 Diabetes Drives Erythrocyte-Induced Vascular Endothelial Dysfunction: A Link to miRNA-210-3p

Type 2 diabetes increases cardiovascular risk, with endothelial dysfunction playing a key role. Prolonged disease duration exacerbates cardiovascular risk, but the underlying mechanisms remain unclear. We previously demonstrated that red blood cells (RBCs) from individuals with type 2 diabetes impair endothelial function via reduced miRNA (miR)-210-3p. We investigated whether disease duration influences RBC-induced endothelial dysfunction and its link to miR-210-3p. RBCs were isolated from diabetic db/db mice of various ages and from humans with newly diagnosed (<1 year) or long-lasting type 2 diabetes (>7 years). Endothelial-dependent relaxation (EDR), miR-210-3p levels, its target protein glycerol-3-phosphate dehydrogenase 2 (GPD2), and oxidative stress marker 4-hydroxynonenal (4-HNE) were assessed. RBCs from 14- and 22-week-old, but not 7-week-old, db/db mice impaired EDR. These RBCs showed similarly reduced miR-210-3p levels and increased vascular GPD2 and 4-HNE expression. RBCs from individuals with long-lasting type 2 diabetes, but not from the newly diagnosed group, impaired EDR. After ≥7 years, RBCs from initially newly diagnosed individuals impaired EDR, which was rescued by miR-210-3p mimic transfection. In contrast, RBCs from healthy subjects did not impair EDR after follow-up. These findings underscore the pivotal role of disease duration for RBC-mediated vascular dysfunction, linked to miR-210-3p downregulation. RBC miR-210-3p may serve as a biomarker for diabetes-related vascular disease.

Red blood cells (RBCs) from older (representing longer duration of diabetes) but not young diabetic mice induce endothelial dysfunction. Protective miRNA-210-3p levels in RBCs are reduced in older diabetic mice compared with young ones. RBCs from individuals with long-lasting (>7 years) but not newly diagnosed type 2 diabetes (<1 year) induce endothelial dysfunction. RBCs from individuals with newly diagnosed type 2 diabetes induce endothelial dysfunction at a >7-year follow up, which is rescued by miRNA-210-3p mimic.