324-OR: Pathway-Specific Role of Insulin in an In Vivo Model of Restenosis

Percutaneous transluminal coronary angioplasty is an effective treatment for stenotic lesions, but restenosis remains as a common adverse effect and contributes to post-angioplasty failure. Patients with type 2 diabetes have higher risk of post-angioplasty restenosis due to insulin resistance. In vitro studies showed that insulin has a vasculoprotective effect on endothelial cells (ECs) which is likely mediated by phosphoinositide 3-kinase (PI3K) /Akt pathway, while its mitogenic effects are mainly manifested on vascular smooth muscle cells (VSMCs) and likely mediated via mitogen-activated protein kinase (MAPK) pathway. Currently, there is not much information about pathway-specificity of insulin’s vascular effects in in vivo models. This study aims to determine the Akt2- and MEK1 (MAPK kinase activator) -mediated effects on neointimal growth in a murine model of restenosis. Akt2/MEK1 floxed mice were crossed with tamoxifen-inducible Cre recombinase under the control of vascular endothelial cadherin (Cdh5) or smooth muscle myosin heavy chain (SMMHC) promoters. Mice were implanted subcutaneously with either insulin pellets (0.U/day) or blank pellets three days prior to femoral artery wire injury surgery. Femoral arteries were collected 28 days after surgery for histology analysis. We found that both neointimal area (NA) and intima-to-media ratio (I/M) were lowered in Akt2 floxed Cre- and and wild type Cre+ control mice following insulin treatment, however, insulin failed to have the same effect in both EC and SMC Akt2 deficient mice. Preliminary data suggest that the effect of insulin on decreasing NA and I/M may be greater in EC MEK1 deficient mice but not in SMC MEK1 deficient mice than controls. These data suggest that both EC and VSMC Akt2 contribute to the beneficial effects of insulin, while EC-specific MEK1 knockdown may accentuate the beneficial effects of insulin.