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

Abstract

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.

Clinical outcomes with reservoir‐based polymer‐free amphilimus‐eluting stents in real‐world patients according to diabetes mellitus and complexity: The INVESTIG8 registry

“…The absence of a persistent durable polymer and the presence of a pure carbon coating in the Cre8 AES assure high biocompatibility and thromboresistance, with accelerated strut endothelialization after stent implantation. Moreover, the antiproliferative effect of rapamycin analogues is attenuated in human insulin‐resistant vascular cells . This attenuation may be overcome by increasing tissue drug concentration.…”

Amphilimus-eluting stents in coronary artery disease: finally, a sweet spot for patients with diabetes mellitus?

“…2 Reasons for this are multifactorial and include cellular conditions favoring vascular smooth muscle cell proliferation, higher levels of vessel wall inflammation and oxidative stress, and possible relative resistance to the antiproliferative agents used on drug eluting stents (DES). 5,6 Improving outcomes of patients with diabetes who undergo coronary stenting is an unmet clinical need. Undoubtedly, the advent of DES technology was a major advance.…”