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

Zhang,Yan; Wang,Qiang; Yang,Dachun; Li,De; Tang,Bing; Yang,Yongjian; Ma,Shuangtao

doi:10.3892/mmr.2014.2141

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

Authors:
- Yan Zhang
- Qiang Wang
- Dachun Yang
- De Li
- Bing Tang
- Yongjian Yang
- Shuangtao Ma
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Affiliations: Department of Cardiology, General Hospital of PLA Chengdu Military Area Command, Chengdu, Sichuan 610083, P.R. China
Published online on: April 11, 2014 https://doi.org/10.3892/mmr.2014.2141
Pages: 2388-2392

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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.

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1	Ohira T and Iso H: Cardiovascular disease epidemiology in Asia: an overview. Circ J. 77:1646–1652. 2013. View Article : Google Scholar : PubMed/NCBI
2	Indermuehle A, Bahl R, Lansky AJ, et al: Drug-eluting balloon angioplasty for in-stent restenosis: a systematic review and meta-analysis of randomised controlled trials. Heart. 99:327–333. 2013. View Article : Google Scholar : PubMed/NCBI
3	Chaabane C, Otsuka F, Virmani R and Bochaton-Piallat ML: Biological responses in stented arteries. Cardiovasc Res. 99:353–363. 2013. View Article : Google Scholar : PubMed/NCBI
4	De Caterina AR, Cuculi F and Banning AP: Incidence, predictors and management of left main coronary artery stent restenosis: a comprehensive review in the era of drug-eluting stents. EuroIntervention. 8:1326–1334. 2013.PubMed/NCBI
5	Pate GE, Lee M, Humphries K, et al: Characterizing the spectrum of in-stent restenosis: implications for contemporary treatment. Can J Cardiol. 22:1223–1229. 2006. View Article : Google Scholar : PubMed/NCBI
6	Ma S, Yang D, Zhang X, et al: Comparison of restenosis rate with sirolimus-eluting stent in STEMI patients with and without diabetes at 6-month angiographic follow-up. Acta Cardiol. 66:603–606. 2011.PubMed/NCBI
7	Trovati M, Doronzo G, Barale C, Vaccheris C, Russo I and Cavalot F: Leptin and vascular smooth muscle cells. Curr Pharm Des. May 14–2013.(Epub ahead of print).
8	Chong ZZ and Maiese K: Mammalian target of rapamycin signaling in diabetic cardiovascular disease. Cardiovasc Diabetol. 11:452012. View Article : Google Scholar : PubMed/NCBI
9	Li W, Li Q, Qin L, et al: Rapamycin inhibits smooth muscle cell proliferation and obstructive arteriopathy attributable to elastin deficiency. Arterioscler Thromb Vasc Biol. 33:1028–1035. 2013. View Article : Google Scholar : PubMed/NCBI
10	Ma S, Yang D, Li D, Tang B and Yang Y: Oleic acid induces smooth muscle foam cell formation and enhances atherosclerotic lesion development via CD36. Lipids Health Dis. 10:532011. View Article : Google Scholar : PubMed/NCBI
11	Jin F, Jiang S, Yang D, et al: Acipimox attenuates atherosclerosis and enhances plaque stability in ApoE-deficient mice fed a palmitate-rich diet. Biochem Biophys Res Commun. 428:86–92. 2012. View Article : Google Scholar : PubMed/NCBI
12	Jiang S, Jin F, Li D, et al: Intermittent hypobaric hypoxia promotes atherosclerotic plaque instability in ApoE-deficient mice. High Alt Med Biol. 14:175–180. 2013. View Article : Google Scholar : PubMed/NCBI
13	Ma S, Yang D, Li D, Tang B, Sun M and Yang Y: Cardiac extracellular matrix tenascin-C deposition during fibronectin degradation. Biochem Biophys Res Commun. 409:321–327. 2011. View Article : Google Scholar : PubMed/NCBI
14	Bangalore S, Kumar S, Fusaro M, et al: Outcomes with various drug eluting or bare metal stents in patients with diabetes mellitus: mixed treatment comparison analysis of 22,844 patient years of follow-up from randomised trials. BMJ. 345:e51702012.
15	Koga J and Aikawa M: Crosstalk between macrophages and smooth muscle cells in atherosclerotic vascular diseases. Vascul Pharmacol. 57:24–28. 2012. View Article : Google Scholar : PubMed/NCBI
16	Jung F, Haendeler J, Goebel C, Zeiher AM and Dimmeler S: Growth factor-induced phosphoinositide 3-OH kinase/Akt phosphorylation in smooth muscle cells: induction of cell proliferation and inhibition of cell death. Cardiovasc Res. 48:148–157. 2000. View Article : Google Scholar : PubMed/NCBI
17	Marx SO, Totary-Jain H and Marks AR: Vascular smooth muscle cell proliferation in restenosis. Circ Cardiovasc Interv. 4:104–111. 2011. View Article : Google Scholar : PubMed/NCBI
18	Scheen AJ, Warzée F and Legrand VM: Drug-eluting stents: meta-analysis in diabetic patients. Eur Heart J. 25:2167–2168. 2004. View Article : Google Scholar : PubMed/NCBI
19	Shan J, Nguyen TB, Totary-Jain H, Dansky H, Marx SO and Marks AR: Leptin-enhanced neointimal hyperplasia is reduced by mTOR and PI3K inhibitors. Proc Natl Acad Sci USA. 105:19006–19011. 2008. View Article : Google Scholar : PubMed/NCBI