Expression of mammalian target of rapamycin in atherosclerotic plaques is decreased under diabetic conditions: a mechanism for rapamycin resistance.

Our previous study demonstrated that diabetes increases in-stent restenosis following rapamycin-eluting stent placement, which was defined as rapamycin resistance. However, the underlying mechanisms of rapamycin resistance remain to be determined. In the present study, male apolipoprotein E-deficient (ApoE-/-) mice were randomly divided into control and diabetic groups. Diabetes was induced by injecting streptozocin (STZ). The hyperglycemic state, defined as a fasting plasma glucose level >13 mmol/l, was maintained for 8 weeks. At the end of the administration, the plasma levels of triglycerides (TG) and total cholesterol (TC) were significantly elevated in the diabetic group compared with the control mice (all P<0.01). The present study revealed that diabetes increased the atherosclerotic plaque size of the aortic root (P<0.01) and the content of vascular smooth muscle cells (VSMCs) in the atherosclerotic lesion (P<0.01). Furthermore, the protein expression and phosphorylation of mammalian target of rapamycin (mTOR), 4E-binding protein 1 and ribosomal S6 kinase 1 (P<0.01) were significantly decreased in the diabetic mice compared with the control group. The decrease in the expression and phosphorylation of mTOR and its downstream kinases may be one of the molecular mechanisms underlying rapamycin resistance.