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

• Published in: Atherosclerosis Vol. 269; pp. 71 - 78
• Main Authors: Lightell, Daniel J., Moss, Stephanie C., Woods, T. Cooper
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier B.V 01.02.2018
• Subjects: Animals; Cell Movement; Cell Proliferation; Cells, Cultured; Cyclin-Dependent Kinase Inhibitor p27 - genetics; Cyclin-Dependent Kinase Inhibitor p27 - metabolism; Diabetes mellitus; Diabetes Mellitus, Type 2 - enzymology; Diabetes Mellitus, Type 2 - genetics; Diabetes Mellitus, Type 2 - pathology; Diabetic Angiopathies - enzymology; Diabetic Angiopathies - genetics; Diabetic Angiopathies - pathology; Diet, High-Fat; Disease Models, Animal; Disease Progression; Femoral Artery - enzymology; Femoral Artery - injuries; Femoral Artery - pathology; Intimal thickening; Mice, Inbred NOD; MicroRNAs - genetics; MicroRNAs - metabolism; miR-221; miR-222; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - metabolism; Muscle, Smooth, Vascular - enzymology; Muscle, Smooth, Vascular - pathology; Myocytes, Smooth Muscle - enzymology; Myocytes, Smooth Muscle - pathology; Neointima; p27Kip1; Signal Transduction; TOR Serine-Threonine Kinases - metabolism; Up-Regulation; Vascular System Injuries - enzymology; Vascular System Injuries - genetics; Vascular System Injuries - pathology; Intimal thickening; p27Kip1; Diabetes mellitus; miR-221; miR-222; p27(Kip1)
• ISSN: 0021-9150; 1879-1484; 1879-1484
• DOI: 10.1016/j.atherosclerosis.2017.12.016

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, p27Kip1, and intimal thickening is promoted by activation of the mammalian Target of Rapamycin to promote degradation of p27Kip1 protein. Recently, we reported that two microRNAs, miR-221 and -222, which promote intimal thickening via down-regulation of mRNA encoding p27Kip1, 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 p27Kip1in a mouse model of diabetes. Comparisons of p27Kip1 signaling in NONcNZO10 mice fed a diabetogenic versus control diet were performed using immunochemistry and real-time PCR. Vascular smooth muscle cells and arteries of diabetic mice exhibited decreased levels of p27Kip1 that derived from destabilization of p27Kip1 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 p27Kip1 mRNA and protein in the arteries of diabetic mice and reduces intimal thickening following wire injury. 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. •Diabetic mice exhibit increased intimal thickening in response to loss of p27Kip1.•Loss of p27Kip1 is due to an increased expression of miRNA-221 and -222.•A change in the molecular regulation of p27Kip1 in response to diabetes is proposed.