Upregulation of miR-221 and -222 in response to increased extracellular signal-regulated kinases 1/2 activity exacerbates neointimal hyperplasia in diabetes mellitus

Abstract

Background and aims: Diabetes is associated with accelerated arterial intimal thickening that contributes to the increased cardiovascular disease seen in this population. In healthy arteries, intimal thickening is inhibited by elevated levels of the cyclin-dependent kinase inhibitor, p27^Kip1, and intimal thickening is promoted by activation of the mammalian Target of Rapamycin to promote degradation of p27^Kip1 protein. Recently, we reported that two microRNAs, miR-221 and -222, which promote intimal thickening via down-regulation of mRNA encoding p27^Kip1, are elevated in the arteries of diabetic patients. To determine if these miRNAs are critical to the increased intimal thickening under diabetic conditions, we examined the regulation of p27^Kip1in a mouse model of diabetes.

Methods: Comparisons of p27^Kip1 signaling in NONcNZO10 mice fed a diabetogenic versus control diet were performed using immunochemistry and real-time PCR.

Results: Vascular smooth muscle cells and arteries of diabetic mice exhibited decreased levels of p27^Kip1 that derived from destabilization of p27^Kip1 mRNA in an extracellular signal response kinase-1/2 (ERK-1/2) dependent manner. The activity of ERK-1/2 is increased in the arteries of diabetic mice and promotes an increase in miR-221 and -222. Inhibition of miR-221 and -222 restores normal levels of p27^Kip1 mRNA and protein in the arteries of diabetic mice and reduces intimal thickening following wire injury.

Conclusions: These data suggest diabetes is accompanied by increases in arterial miR-221 and -222 expression that promotes intimal thickening. Inhibition of the increased miR-221 and -222 may be efficacious in the prevention of the cardiovascular complications of diabetes.

Keywords: Diabetes mellitus; Intimal thickening; miR-221; miR-222; p27(Kip1).