Inhibition of miR-200c Restores Endothelial Function in Diabetic Mice Through Suppression of COX-2

Diabetes. 2016 May;65(5):1196-207. doi: 10.2337/db15-1067. Epub 2016 Jan 28.


Endothelial dysfunction plays a crucial role in the development of diabetic vasculopathy. Our initial quantitative PCR results showed an increased miR-200c expression in arteries from diabetic mice and patients with diabetes. However, whether miR-200c is involved in diabetic endothelial dysfunction is unknown. Overexpression of miR-200c impaired endothelium-dependent relaxations (EDRs) in nondiabetic mouse aortas, whereas 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 that miR-200c upregulated COX-2 expression in endothelial cells through suppression of ZEB1 and increased production of prostaglandin E2, which also reduced EDR. This study demonstrates for the first time to our knowledge 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Animals
  • Aorta, Thoracic / metabolism
  • Aorta, Thoracic / pathology
  • Aorta, Thoracic / physiopathology
  • Cell Line
  • Cells, Cultured
  • Cyclooxygenase 2 / chemistry
  • Cyclooxygenase 2 / metabolism*
  • Diabetes Mellitus / metabolism*
  • Diabetes Mellitus / pathology
  • Diabetes Mellitus / physiopathology
  • Endothelium, Vascular / metabolism*
  • Endothelium, Vascular / pathology
  • Endothelium, Vascular / physiopathology
  • Gene Expression Regulation*
  • Humans
  • In Vitro Techniques
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Mutant Strains
  • MicroRNAs / antagonists & inhibitors*
  • MicroRNAs / metabolism
  • Middle Aged
  • RNA / metabolism
  • RNA Interference
  • Renal Artery / metabolism
  • Renal Artery / pathology
  • Renal Artery / physiopathology
  • Vasodilation
  • Zinc Finger E-box-Binding Homeobox 1 / antagonists & inhibitors
  • Zinc Finger E-box-Binding Homeobox 1 / genetics
  • Zinc Finger E-box-Binding Homeobox 1 / metabolism


  • MIRN200 microRNA, human
  • MicroRNAs
  • Mirn200 microRNA, mouse
  • RNA, recombinant
  • Zinc Finger E-box-Binding Homeobox 1
  • RNA
  • Ptgs2 protein, mouse
  • Cyclooxygenase 2
  • PTGS2 protein, human