Inhibition of miR-200c restores endothelial function in diabetic mice through suppression of COX-2

Endothelial dysfunction plays a crucial role in the development of diabetic vasculopathy. Our initial qPCR results showed an increased miR-200c expression in arteries from diabetic mice and patients. However, whether miR-200c is involved in diabetic endothelial dysfunction is unknown. Overexpression of miR-200c impaired endothelium-dependent relaxations (EDRs) in non-diabetic mouse aortas, while suppression of miR-200c by anti-miR-200c enhanced EDRs in diabetic db/db mice. MiR-200c suppressed ZEB1 expression and ZEB1 overexpression ameliorated endothelial dysfunction induced by miR-200c or associated with diabetes. More importantly, overexpression of anti-miR-200c or ZEB1 in vivo attenuated miR-200c expression and improved EDRs in db/db mice. Mechanistic study with the use of COX-2 -/- mice revealed that COX-2 mediated miR-200c-induced endothelial dysfunction and miR-200c up-regulated COX-2 expression in endothelial cells via suppression of ZEB1 and increased production of PGE 2 which also reduced EDR. In conclusion, our study demonstrates for the first time that miR-200c is a new mediator of diabetic endothelial dysfunction and inhibition of miR-200c rescues EDRs in diabetic mice. These new findings suggest the potential usefulness of miR-200c as the target for drug intervention against diabetic vascular complications.