Altered red blood cell (RBC) function can lead to vascular damage in type 2 diabetes mellitus (T2DM). The results from a research in red blood cells from T2DM patients and from diabetic mice, and experiments in live diabetic (db/db) mice, have now shown that this effect is caused by low RBC levels of a microRNA known as miRNA-210. Restoring RBC miRNA-210 levels in diabetic mice prevented the development of RBC-mediated vascular dysfunction. The Karolinska Institutet researchers suggest their findings could point to new therapeutic approaches to preventing vascular damage in T2DM patients.

“The findings demonstrate a previously unrecognized cause of vascular injury in type 2 diabetes,” said Zhichao Zhou, MD, PhD, researcher in the Karolinska Institutet (KI) Department of Medicine, who is co-corresponding author of the team’s published paper in Diabetes. “We hope that the results will pave the way for new therapies that increase red blood cell microRNA-210 levels and thereby prevent vascular injury in patients with type 2 diabetes. It is well known that patients with type 2 diabetes have an increased risk of cardiovascular disease.” The scientists, including research lead John Pernow MD, PhD, at the Karolinska Institutet Department of Medicine, and collaborators at the KI, and at the Technical University of Munich, reported on their findings in a paper titled, “Downregulation of Erythrocyte miR-210 Induced Endothelial Dysfunction in Type 2 Diabetes.”

Over time type 2 diabetes may damage blood vessels, which could lead to life-threatening complications such as heart attack and stroke. However, the disease mechanisms underlying cardiovascular injury in type 2 diabetes are largely unknown and there is currently a lack of treatments to prevent such injuries. “Cardiovascular complications are major clinical problems in type 2 diabetes mellitus (T2DM), and patients with T2DM have poorer clinical outcomes following a cardiovascular event such as myocardial infarction,” the authors noted. And while endothelial dysfunction plays a key role in the development of vascular complications in T2DM, they further pointed out, “… key events triggering the endothelial dysfunction in T2DM remain to be clearly identified.”

During recent years research has shown that the red blood cells—which play a crucial role in cardiovascular homeostasis and contribute to vascular function independently from their function as oxygen carriers—become dysfunctional in type 2 diabetes and can act as mediators of vascular complications. However, as the authors also noted, “… key mechanisms underlying the interaction of RBCs with the vasculature remain largely unknown.”

MicroRNAs are non-coding RNAs of 19–25 nucleotides in length that can act as fundamental post-transcriptional regulators of gene expression and function in cardiometabolic diseases, including T2DM. “Due to their stability in the circulation and conservation across species, miRNAs can serve as biomarkers as well as mediators of vascular complications in T2DM,” the team continued. “RBCs, which constitute ~45% of the blood volume (hematocrit), are known to contain abundant and diverse miRNAs.”

Studies have shown that miR-210 plays a crucial role in maintaining cardiovascular homeostasis, and acts as a protective factor against vascular and cardiac ischemic injury in mice. The team hypothesized that downregulation of RBC miR-210 might induce endothelial dysfunction in T2DM. “However, the expression of miR-210 in RBCs remains unexplored and it is unknown whether dysregulated miR-210 expression in RBCs is of importance for endothelial dysfunction in T2DM,” they pointed out.

For their reported study the team focused on RBCs taken from patients with type 2 diabetes and from diabetic mice, to examine which molecular changes in the red blood cells could explain these harmful effects in type 2 diabetes. They found that levels of miRNA-210 were markedly reduced in red blood cells from 36 patients with type 2 diabetes, compared with red blood cells of 32 healthy subjects. This reduction in microRNA-210 caused alterations in specific vascular protein levels, and impaired blood vessel endothelial cell function.

In laboratory experiments, restoration of microRNA-210 levels in red blood cells prevented the development of vascular injury via specific molecular changes. “A major finding in our study is that rescue of miR-210 levels in RBCs from patients with T2DM attenuated endothelial dysfunction, while inhibition of miR-210 in RBCs from healthy subjects led to impairment of endothelial function,” the team wrote.

And in live diabetic mice, rescue of miR-210 prevented the development of endothelial dysfunction, “ … identifying RBC miR-210 as a potential target for the prevention of endothelial dysfunction in T2DM,” the authors commented. “The protective role of RBC miR-210 was further confirmed using miR-210 KO [knockout] mice. Further, in vivo administration of miR-210 mimic to db/db mice, which resulted in elevation of miR-210 levels in db/db RBCs, completely prevented the development of endothelial dysfunction induced by RBCs from these db/db mice.”

The findings indicated that reactive oxygen species (ROS), and PTP1B—an enzyme regulating insulin signaling, and which is a direct target of miR-210—are involved in endothelial dysfunction triggered by the downregulation of miR-210. “In conclusion, we demonstrate a novel mechanism behind vascular dysfunction in T2DM by which downregulation of miR-210 in RBCs induces endothelial dysfunction via interaction with vascular PTP1B and ROS,” they wrote. “Our findings clearly suggest that strategies to increase RBC miR-210 levels have the potential to serve as an effective therapy for the treatment of endothelial dysfunction in patients with T2DM.”

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