New research has found one of the smallest entities¹（实体，存在） in the human genome, micro-RNA, could increase the risk of limb amputation²（截肢） in diabetic patients who have poor blood flow. The study by Dr Andrea Caporali and colleagues in Professor Costanza Emanueli's research group in the Regenerative Medicine Section of the School of Clinical Sciences at the University of Bristol was funded by the Medical Research Council and is published online in Circulation: Journal of the American Heart Association.

The research group have shown in an experimental cell study that conditions mimicking⁴ diabetes⁵ and a lack of blood supply to a tissue increased a particular miRNA (miRNA-503) and impaired⁶ the ability of endothelial cells（内皮细胞） , which line the interior surface of blood vessels⁸. Micro-RNAs (miRNAs) are small sections of ribonucleic acid（核糖核酸） (RNA) that can inhibit⁹ many genes¹⁰.

Alternatively, slowing down miRNA-503 improved the capability¹¹ of endothelial cells to duplicate and form into networks of small blood vessels. The researchers showed that microRNA-503 reduces cell growth and prevents the formation of blood vessels by direct binding¹² and inhibition of cyclin E1 and Cdc25 mRNA.

Costanza Emanueli, Professorial Research Fellow in Vascular¹³ Pathology & Regeneration, said: "Because each miRNA can regulate many genes, they represent an exciting new target to correct diseases that have complex underlying¹⁴ mechanisms¹⁵, like diabetes, rather than trying to target one specific gene³. Our study is the first to provide evidence for a role of miRNAs in diabetes-induced defects in reparative angiogenesis（血管生成） ."

The team subsequently investigated miR-503 and target gene expression in muscular specimens¹⁶ from the amputated ischaemic legs of diabetic patients. As controls, calf¹⁷ biopsies of non-diabetic and non-ischemic patients undergoing saphenous vein¹⁸ stripping were used. In diabetic muscles, miR-503 expression was remarkably¹⁹ higher, and plasma²⁰ miR-503 levels were also elevated in the diabetic subjects.

Finally, using mouse models of diabetes and limb ischaemia（局部贫血） , the researchers found that inhibition of the miRNA-503 (using a "decoy miRNA") could restore-post-ischaemic blood flow recovery. The findings of this study highlight important clinical implications of miR-503 in diabetes-associated vascular complications.

In early diabetes, high blood glucose²¹（血糖） levels damage blood vessels leading to lack of blood flow (ischaemia). Such ischaemic complications are the leading cause of disease and death in diabetic patients. In limbs, lack of blood flow can result in non-healing ulcers²²（溃疡） and, in diabetic patients, the ischaemic disease follows an unalterable course and limb amputation is too often the eventual²³ remedy.

Tissues can recover from lack of blood flow by new blood vessel⁷ growth (angiogenesis血管生成), which restores blood supply to the tissue (reperfusion). However, diabetes harms the restoration of the flow of blood to a previously²⁴ ischemic tissue, by mechanisms that are not fully²⁵ understood, and so a better understanding of the molecular²⁶ mechanisms underpinning²⁷ diabetes-associated vascular complications is urgently needed to improve therapeutic²⁸ options.