Dysregulation of the Mammalian Target of Rapamycin and p27(Kip1) Promotes Intimal Hyperplasia in Diabetes Mellitus

The proliferation and migration of vascular smooth muscle cells (VSMCs) in the intima of an artery, known as intimal hyperplasia, is an important component of cardiovascular diseases. This is seen most clearly in the case of in-stent restenosis, where drug eluting stents are used to deliver agents that prevent VSMC proliferation and migration. One class of agents that are highly effective in the prevention of in-stent restenosis is the mammalian Target of Rapamycin (mTOR) inhibitors. Inhibition of mTOR blocks protein synthesis, cell cycle progression, and cell migration. Key to the effects on cell cycle progression and cell migration is the inhibition of mTOR-mediated degradation of p27(Kip1) protein. p27(Kip1) is a cyclin dependent kinase inhibitor that is elevated in quiescent VSMCs and inhibits the G(1) to S phase transition and cell migration. Under normal conditions, vascular injury promotes degradation of p27(Kip1) protein in an mTOR dependent manner. Recent reports from our lab suggest that in the presence of diabetes mellitus, elevation of extracellular signal response kinase activity may promote decreased p27(Kip1) mRNA and produce a relative resistance to mTOR inhibition. Here we review these findings and their relevance to designing treatments for cardiovascular disease in the presence of diabetes mellitus.