Abstract 19050: Accelerated Neointimal Hyperplasia in a Diabetic Mouse Model via Elevated microRNA-221/222

Introduction: Neointimal hyperplasia is increased in the diabetic population, promoting accelerated plaque development and an increased risk of stroke and myocardial infarction. Two microRNA, miR-221/222, that are known to promote neointimal hyperplasia in response to vascular injury through down regulation of the cyclin dependent kinase inhibitor, p27Kip1, are elevated in the internal mammary arteries of diabetic subjects. We hypothesized that miR-221/222 would be elevated in the arteries of a mouse model of diabetes and that this increase in miR-221/222 would promote a decrease in p27Kip1 and an increase in neointimal hyperplasia following vascular injury. Methods: Femoral artery wire injury coupled with perivascular local delivery of a low dose of either non-targeting (NT) or miR-221/222 targeting antisense oligonucleotides (AS) was performed in NONcNZO10 mice fed a diabetes inducing diet (DM) or normal chow (ND). We compared neointimal hyperplasia and the expression of miR-221/222 and p27Kip1 in DM and ND mice in the presence and absence of AS treatment. Results: DM mice exhibited a ~2 fold elevation in expression of miR-221/222 both pre- and post-injury compared to ND mice. This was coupled with significant decreases in p27Kip1 mRNA and protein as well as the decreases in the mRNA for two additional targets of miR-221/222, c-Kit and p53 up-regulated modulator of apoptosis. In DM mice AS treatment reduced miR-221/222 expression (Figure 1A) and restored normal p27Kip1 mRNA and protein levels, with no effect in the ND mice. Similarly, neointimal hyperplasia was significantly elevated in the NT treated arteries of the DM mice, but AS treatment reduced neointimal hyperplasia to levels comparable to the ND mice (Figure 1B). Conclusions: We conclude that diabetes is accompanied by an increased arterial expression of miR-221/222 that in turn accelerates neointimal hyperplasia in response to arterial injury.