Relative resistance to Mammalian target of rapamycin inhibition in vascular smooth muscle cells of diabetic donors.

BACKGROUND

Diabetes mellitus is associated with an increased risk of cardiovascular disease. Intimal thickening, a component of cardiovascular disease, entails the proliferation and migration of vascular smooth muscle cells (VSMCs). Inhibition of the mammalian target of rapamycin (mTOR) blocks VSMC proliferation, in part through an increase in the cyclin-dependent kinase inhibitor, p27(Kip1). The use of mTOR inhibitors, such as rapamycin, is effective clinically in inhibiting intimal thickening. This efficacy is reduced in diabetic subjects, however, suggesting a change in the role of the mTOR pathway in intimal thickening under diabetic conditions.

METHODS

To examine whether diabetes induced changes in the role of mTOR in VSMC proliferation, we compared the response to rapamycin of human coronary artery VSMCs from diabetic (DM-huCASMC [human coronary artery smooth muscle cell]) and nondiabetic (ND-huCASMC) subjects.

RESULTS

The DM-huCASMCs exhibited a relative resistance to rapamycin's inhibition of proliferation. Activation of the mTOR effector p70(S6kinase) was inhibited in rapamycin-treated DM-huCASMCs as in ND-huCASMCs. While ND-huCASMCs exhibited the normal increase in p27(Kip1) in response to rapamycin treatment, the DM-huCASMCs did not. Additionally, activation of the extracellular signal response kinase pathway was increased in the DM-huCASMCs, suggesting a potential pathway mediating the mTOR-independent decrease in p27(Kip1).

CONCLUSION

We conclude that diabetes is accompanied by a relative resistance to the effects of mTOR inhibition on VSMC proliferation through a loss of mTOR's effects on p27(Kip1) levels. These data provide insight into the effects of insulin resistance on the role of mTOR in regulating intimal thickening.