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Simvastatin Suppresses Apoptosis in Vulnerable Atherosclerotic Plaques Through Regulating the Expression of p53, Bcl-2 and Bcl-xL

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Abstract

Purpose

Simvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, has antioxidant and anti-inflammatory properties that are independent of lipid-lowering abilities. This experiment was carried out to explore the effects of simvastatin on apoptosis in vulnerable atherosclerotic plaques of apoE-deficient mice.

Methods and results

Eight weeks-old apoE−/− mice were fed a Western-type diet. Vulnerable atherosclerotic lesions were formed in the branchiocephalic artery at the age of 30-weeks, before simvastatin administration for 8 weeks. Simvastatin did neither affect the levels of plasma glucose and lipids, nor the size of atherosclerotic lesions. Analysis of plaque composition showed that simvastatin decreased the area of lipid core and increased the amounts of macrophages and smooth muscle cells in atherosclerotic plaques of apoE−/− mice. In addition, simvastatin down-regulated the expression of vascular cell adhesion molecule-1 (VCAM-1) by both inhibition of nuclear factor kappa B (NF-кB) activation and suppression of the expression of the receptor for advanced glycation end products (RAGE). Moreover, we found that simvastatin administration led to reduced TUNEL-positive cells in the aortic root lesions, accompanied by up-regulation of Bcl-2 and Bcl-xL expression, and decreased P53 expression as shown by Western blot.

Conclusion

In the present study, we show novel data to suggest that simvastatin could suppress apoptosis in vulnerable atherosclerotic plaques of apoE−/− mice by regulating the expression of apoptosis-related proteins, such as p53, Bcl-2 and Bcl-xL.

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References

  1. Burke AP, Kolodgie FD, Farb A, Weber D, Virmani R. Morphological predictors of arterial remodeling in coronary atherosclerosis. Circulation. 2002;105:297–303.

    Article  PubMed  Google Scholar 

  2. Thorp E, Tabas I. Mechanisms and consequences of efferocytosis in advanced atherosclerosis. J Leukoc Biol. 2009;86:1089–95.

    Article  PubMed  CAS  Google Scholar 

  3. Seimon T, Tabas I. Mechanisms and consequences of macrophage apoptosis in atherosclerosis. J Lipid Res. 2009;50:S382–387.

    Article  PubMed  Google Scholar 

  4. Ihling C, Menzel G, Wellens E, Mönting JS, Schaefer HE, Zeiher AM. Topographical association between the cyclin-dependent kinases inhibitor P21, p53 accumulation, and cellular proliferation in human atherosclerotic tissue. Arterioscler Thromb Vasc Biol. 1997;17:2218–24.

    Article  PubMed  CAS  Google Scholar 

  5. von der Thüsen JH, van Vlijmen BJ, Hoeben RC, et al. Induction of atherosclerotic plaque rupture in apolipoprotein E−/− mice after adenovirus-mediated transfer of p53. Circulation. 2002;105:2064–70.

    Article  PubMed  Google Scholar 

  6. Tabas I. p53 and atherosclerosis. Circ Res. 2001;88:747–9.

    Article  PubMed  CAS  Google Scholar 

  7. Thorp E, Li Y, Bao L, et al. Brief report: increased apoptosis in advanced atherosclerotic lesions of Apo E−/− mice lacking macrophage Bcl-2. Arterioscler Thromb Vasc Biol. 2009;29:169–72.

    Article  PubMed  CAS  Google Scholar 

  8. Gautier EL, Huby T, Witztum JL, et al. Macrophage apoptosis exerts divergent effects on atherogenesis as a function of lesion stage. Circulation. 2009;119:1795–804.

    Article  PubMed  CAS  Google Scholar 

  9. Liu J, Thewke DP, Su YR, Linton MF, Fazio S, Sinensky MS. Reduced macrophage apoptosis is associated with accelerated atherosclerosis in low-density lipoprotein receptor-null mice. Arterioscler Thromb Vasc Biol. 2005;25:174–9.

    PubMed  CAS  Google Scholar 

  10. Wierzbicki AS, Poston R, Ferro A. The lipid and non-lipid effects of statins. Pharmacol Ther. 2003;99:95–112.

    Article  PubMed  CAS  Google Scholar 

  11. Marzilli M. Pleiotropic effects of statins: evidence for benefits beyond LDL-cholesterol lowering. Am J Cardiovasc Drugs. 2010;10:S3–9.

    Article  Google Scholar 

  12. Zuckerman SH, Evans GF, Schelm JA, Eacho PI, Sandusky G. Estrogen-mediated increases in LDL cholesterol and foam cell-containing lesions in human ApoB100xCETP transgenic mice. Arterioscler Thromb Vasc Biol. 1999;19:1476–83.

    Article  PubMed  CAS  Google Scholar 

  13. Bea F, Blessing E, Bennett B, Levitz M, Wallace EP, Rosenfeld ME. Simvastatin promotes atherosclerotic plaque stability in apoE-deficient mice independently of lipid lowering. Arterioscler Thromb Vasc Biol. 2002;22:1832–7.

    Article  PubMed  CAS  Google Scholar 

  14. Thorp E, Cui D, Schrijvers DM, Kuriakose G, Tabas I. Mertk receptor mutation reduces efferocytosis efficiency and promotes apoptotic cell accumulation and plaque necrosis in atherosclerotic lesions of apoe−/− mice. Arterioscler Thromb Vasc Biol. 2008;28:1421–8.

    Article  PubMed  CAS  Google Scholar 

  15. Tekabe Y, Li Q, Rosario R, et al. Development of receptor for advanced glycation end products-directed imaging of atherosclerotic plaque in a murine model of spontaneous atherosclerosis. Circ Cardiovasc Imaging. 2008;1:212–9.

    Article  PubMed  Google Scholar 

  16. Goldin A, Beckman JA, Schmidt AM, Creager MA. Advanced glycation end products: sparking the development of diabetic vascular injury. Circulation. 2006;114:597–605.

    Article  PubMed  CAS  Google Scholar 

  17. Bierhaus A, Schiekofer S, Schwaninger M, et al. Diabetes-associated sustained activation of the transcription factor nuclear factor-кB. Diabetes. 2001;50:2792–808.

    Article  PubMed  CAS  Google Scholar 

  18. Basta G. Receptor for advanced glycation endproducts and atherosclerosis: From basic mechanisms to clinical implications. Atherosclerosis. 2008;196:9–21.

    Article  PubMed  CAS  Google Scholar 

  19. Sun L, Ishida T, Yasuda T, et al. RAGE mediates oxidized LDL-induced pro-inflammatory effects and atherosclerosis in non-diabetic LDL receptor-deficient mice. Cardiovasc Res. 2009;82:371–81.

    Article  PubMed  CAS  Google Scholar 

  20. Harja E, Bu DX, Hudson BI, et al. Vascular and inflammatory stresses mediate atherosclerosis via RAGE and its ligands in apoE−/− mice. J Clin Invest. 2008;118:183–94.

    Article  PubMed  CAS  Google Scholar 

  21. Yan ZQ, Hansson GK. Innate immunity, macrophage activation, and atherosclerosis. Immunol Rev. 2007;219:187–203.

    Article  PubMed  CAS  Google Scholar 

  22. Merched AJ, Williams E, Chan L. Macrophage-specific p53 expression plays a crucial role in atherosclerosis development and plaque remodeling. Arterioscler Thromb Vasc Biol. 2003;23:1608–14.

    Article  PubMed  CAS  Google Scholar 

  23. Okada S, Zhang H, Hatano M, Tokuhisa T. A physiologic role of Bcl-xL induced in activated macrophages. J Immunol. 1998;160:2590–6.

    PubMed  CAS  Google Scholar 

  24. Chatterjee D, Han Z, Mendoza J, et al. Monocytic differentiation of HL-60 promyelocytic leukemia cells correlates with the induction of Bcl-xL. Cell Growth Differ. 1997;8:1083–9.

    PubMed  CAS  Google Scholar 

  25. Antignani A, Youle RJ. The cytokine, granulocyte-macrophage colony-stimulating factor (GM-CSF), can deliver Bcl-XL as an extracellular fusion protein to protect cells from apoptosis and retain differentiation induction. J Biol Chem. 2007;282:11246–54.

    Article  PubMed  CAS  Google Scholar 

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Funding

This work was supported by grants from National Basic Research Program of China (2012CB517502) and National Natural Science Foundation of China (81070634).

Conflict of interest

None declared.

Author information

Authors and Affiliations

  1. The Key Laboratory of Geriatrics, Beijing Hospital & Beijing Institute of Geriatrics, Ministry of Health, Beijing, 100730, China

    Weiwei Qin, Yonggang Lu, Tao Shen, Lin Dou, Yong Man, Shu Wang & Jian Li

  2. The Second Hospital of Shanxi Medical University, Taiyuan, 030001, China

    Weiwei Qin, Chuanshi Xiao & Yunfei Bian

  3. Shanghai PuNan Hospital, Shanghai, 200125, China

    Chengyan Zhan

Authors
  1. Weiwei Qin
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  2. Yonggang Lu
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  3. Chengyan Zhan
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  4. Tao Shen
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  5. Lin Dou
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  6. Yong Man
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  7. Shu Wang
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  8. Chuanshi Xiao
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  9. Yunfei Bian
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  10. Jian Li
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Corresponding authors

Correspondence to Yunfei Bian or Jian Li.

Additional information

Weiwei Qin, Yonggang Lu, and Chengyan Zhan contributed equally to this work.

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Qin, W., Lu, Y., Zhan, C. et al. Simvastatin Suppresses Apoptosis in Vulnerable Atherosclerotic Plaques Through Regulating the Expression of p53, Bcl-2 and Bcl-xL. Cardiovasc Drugs Ther 26, 23–30 (2012). https://doi.org/10.1007/s10557-011-6347-z

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  • DOI: https://doi.org/10.1007/s10557-011-6347-z

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