Simvastatin attenuates TNF‑α‑induced apoptosis in endothelial progenitor cells via the upregulation of SIRT1

  • Authors:
    • Gang Du
    • Yunlin Song
    • Tao Zhang
    • Long Ma
    • Ning Bian
    • Xiaoming Chen
    • Jianyi Feng
    • Qing Chang
    • Zicheng Li
  • View Affiliations

  • Published online on: April 9, 2014     https://doi.org/10.3892/ijmm.2014.1740
  • Pages: 177-182
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

Endothelial progenitor cells (EPCs) originate from the bone marrow and can be classified as either early or late EPCs. The focus of this study was on late EPCs, as they play an important role in angiogenesis and vascular proliferation. Evidence suggests that inflammatory and oxidative changes can increase EPC apoptosis. Of note, tumor necrosis factor-α (TNF-α) is a contributing risk factor to the development of atherosclerosis and plays a key role as both an inflammatory mediator and an inducer of apoptosis in endothelial cells. Additionally, a member of the sirtuin family, silent information regulator type-1 (SIRT1), promotes cell survival by repressing p53- and non-p53-dependent apoptosis in response to DNA damage and oxidative stress. Statins have also been shown to play a key role in the prevention of endothelial apoptosis and senescence via their lipid-lowering and anti-inflammatory actions. However, there is little evidence that statins themselves attenuate EPC apoptosis induced by TNF-α. The aim of this study was to demonstrate the effectiveness of one of the most commonly used statins, simvastatin, on decreasing TNF-α-induced apoptosis in EPCs. The results indicated that SIRT1 protein expression was decreased by TNF-α in a time- and dose-dependent manner and that while TNF-α caused a marked increase in the percentage of apoptotic EPCs, application of simvastatin decreased this percentage. A high concentration of simvastatin promoted the expression of SIRT1 and increased the proliferation of EPCs. In conclusion, findings of this study showed that simvastatin is crucial in counteracting the TNF-α-induced apoptosis of EPCs and that this protection may involve the actions of SIRT1.

References

1 

Rouhl RP, van Oostenbrugge RJ, Damoiseaux J, Tervaert JW and Lodder J: Endothelial progenitor cell research in stroke: a potential shift in pathophysiological and therapeutical concepts. Stroke. 39:2158–2165. 2008. View Article : Google Scholar : PubMed/NCBI

2 

Decano JL, Moran AM, Giordano N, Ruiz-Opazo N and Herrera VL: Analysis of CD45- [CD34+/KDR+] endothelial progenitor cells as juvenile protective factors in a rat model of ischemic-hemorrhagic stroke. PLoS One. 8:e552222013.

3 

Huang H, Huang F and Huang JP: Transplantation of bone marrow-derived endothelial progenitor cells overexpressing Delta-like-4 enhances functional neovascularization in ischemic myocardium. Mol Med Rep. 8:1556–1562. 2013.

4 

Thal MA, Krishnamurthy P, Mackie AR, et al: Enhanced angiogenic and cardiomyocyte differentiation capacity of epigenetically reprogrammed mouse and human endothelial progenitor cells augments their efficacy for ischemic myocardial repair. Circ Res. 111:180–190. 2012. View Article : Google Scholar

5 

Patschan D, Hildebrandt A, Rinneburger J, et al: The hormone melatonin stimulates renoprotective effects of ‘early outgrowth’ endothelial progenitor cells in acute ischemic kidney injury. Am J Physiol Renal Physiol. 302:F1305–F1312. 2012.PubMed/NCBI

6 

Bouchentouf M, Forner K, Cuerquis J, et al: A novel and simplified method of culture of human blood-derived early endothelial progenitor cells for the treatment of ischemic vascular disease. Cell Transplant. 20:1431–1443. 2011. View Article : Google Scholar : PubMed/NCBI

7 

Głowińska-Olszewska B, Luczyński W and Bossowski A: Endothelial progenitor cells as a new marker of endothelial function with respect to risk of cardiovascular disorders. Postepy Hig Med Dosw (Online). 65:8–15. 2011.(In Polish).

8 

Shantsila E, Watson T and Lip GY: Endothelial progenitor cells in cardiovascular disorders. J Am Coll Cardiol. 49:741–752. 2007. View Article : Google Scholar

9 

Sun JY, Zhai L, Li QL, et al: Effects of ACE inhibition on endothelial progenitor cell mobilization and prognosis after acute myocardial infarction in type 2 diabetic patients. Clinics (Sao Paulo). 68:665–673. 2013. View Article : Google Scholar : PubMed/NCBI

10 

Sandri M, Beck EB, Adams V, et al: Maximal exercise, limb ischemia, and endothelial progenitor cells. Eur J Cardiovasc Prev Rehabil. 18:55–64. 2011.PubMed/NCBI

11 

Aicher A, Heeschen C, Sasaki K, Urbich C, Zeiher AM and Dimmeler S: Low-energy shock wave for enhancing recruitment of endothelial progenitor cells: a new modality to increase efficacy of cell therapy in chronic hind limb ischemia. Circulation. 114:2823–2830. 2006. View Article : Google Scholar : PubMed/NCBI

12 

Jiménez-Navarro MF, González FJ, Caballero-Borrego J, et al: Coronary disease extension determines mobilization of endothelial progenitor cells and cytokines after a first myocardial infarction with ST elevation. Rev Esp Cardiol. 64:1123–1129. 2011.(In Spanish).

13 

Bonello L, Harhouri K, Baumstarck K, et al: Mobilization of CD34+ KDR+ endothelial progenitor cells predicts target lesion revascularization. J Thromb Haemost. 10:1906–1913. 2012.

14 

Kim JY, Park YJ, Kim KJ, Choi JJ, Kim WU and Cho CS: Osteoprotegerin causes apoptosis of endothelial progenitor cells by induction of oxidative stress. Arthritis Rheum. 65:2172–2182. 2013. View Article : Google Scholar : PubMed/NCBI

15 

Chen J, Huang L, Song M, Yu S, Gao P and Jing J: C-reactive protein upregulates receptor for advanced glycation end products expression and alters antioxidant defenses in rat endothelial progenitor cells. J Cardiovasc Pharmacol. 53:359–367. 2009. View Article : Google Scholar

16 

Skoog T, Dichtl W, Boquist S, et al: Plasma tumour necrosis factor-alpha and early carotid atherosclerosis in healthy middle-aged men. Eur Heart J. 23:376–383. 2002. View Article : Google Scholar : PubMed/NCBI

17 

Ruan W, Xu JM, Li SB, Yuan LQ and Dai RP: Effects of down-regulation of microRNA-23a on TNF-α-induced endothelial cell apoptosis through caspase-dependent pathways. Cardiovasc Res. 93:623–632. 2012.PubMed/NCBI

18 

Markelic M, Velickovic K, Golic I, et al: Endothelial cell apoptosis in brown adipose tissue of rats induced by hyperinsulinaemia: the possible role of TNF-α. Eur J Histochem. 55:e342011.PubMed/NCBI

19 

Nystrom T, Nygren A and Sjoholm A: Increased levels of tumour necrosis factor-alpha (TNF-alpha) in patients with Type II diabetes mellitus after myocardial infarction are related to endothelial dysfunction. Clin Sci (Lond). 110:673–681. 2006. View Article : Google Scholar

20 

Speciale A, Canali R, Chirafisi J, Saija A, Virgili F and Cimino F: Cyanidin-3-O-glucoside protection against TNF-α-induced endothelial dysfunction: involvement of nuclear factor-κB signaling. J Agric Food Chem. 58:12048–12054. 2010.

21 

Henrich D, Seebach C, Wilhelm K and Marzi I: High dosage of simvastatin reduces TNF-alpha-induced apoptosis of endothelial progenitor cells but fails to prevent apoptosis induced by IL-1beta in vitro. J Surg Res. 142:13–19. 2007. View Article : Google Scholar : PubMed/NCBI

22 

Seeger FH, Haendeler J, Walter DH, et al: p38 mitogen-activated protein kinase downregulates endothelial progenitor cells. Circulation. 111:1184–1191. 2005. View Article : Google Scholar : PubMed/NCBI

23 

Ziedén B and Olsson AG: The role of statins in the prevention of ischemic stroke. Curr Atheroscler Rep. 7:364–368. 2005.

24 

Margaritis M, Channon KM and Antoniades C: Statins as regulators of redox state in the vascular endothelium: beyond lipid lowering. Antioxid Redox Signal. 20:1198–1215. 2014. View Article : Google Scholar : PubMed/NCBI

25 

Zhu Y, Casey PJ, Kumar AP and Pervaiz S: Deciphering the signaling networks underlying simvastatin-induced apoptosis in human cancer cells: evidence for non-canonical activation of RhoA and Rac1 GTPases. Cell Death Dis. 4:e5682013. View Article : Google Scholar

26 

Piechota-Polanczyk A, Goraca A, Demyanets S, et al: Simvastatin decreases free radicals formation in the human abdominal aortic aneurysm wall via NF-κB. Eur J Vasc Endovasc Surg. 44:133–137. 2012.

27 

Fuhrmeister J, Tews M, Kromer A and Moosmann B: Prooxidative toxicity and selenoprotein suppression by cerivastatin in muscle cells. Toxicol Lett. 215:219–227. 2012. View Article : Google Scholar : PubMed/NCBI

28 

Hoffmann G, Breitenbücher F, Schuler M and Ehrenhofer-Murray AE: A novel sirtuin 2 (SIRT2) inhibitor with p53-dependent pro-apoptotic activity in non-small cell lung cancer. J Biol Chem. 289:5208–5216. 2014. View Article : Google Scholar : PubMed/NCBI

29 

Nihal M, Ahmad N and Wood GS: SIRT1 is upregulated in cutaneous T-cell lymphoma and its inhibition induces growth arrest and apoptosis. Cell Cycle. 13:632–640. 2014. View Article : Google Scholar : PubMed/NCBI

30 

Hori YS, Kuno A, Hosoda R and Horio Y: Regulation of FOXOs and p53 by SIRT1 modulators under oxidative stress. PLoS One. 8:e738752013. View Article : Google Scholar : PubMed/NCBI

31 

Kim S, Bi X, Czarny-Ratajczak M, et al: Telomere maintenance genes SIRT1 and XRCC6 impact age-related decline in telomere length but only SIRT1 is associated with human longevity. Biogerontology. 13:119–131. 2012. View Article : Google Scholar : PubMed/NCBI

32 

Kok SH, Lin LD, Hou KL, et al: Simvastatin inhibits cysteine-rich protein 61 expression in rheumatoid arthritis synovial fibroblasts through the regulation of sirtuin-1/FoxO3a signaling. Arthritis Rheum. 65:639–649. 2013. View Article : Google Scholar : PubMed/NCBI

33 

Ota H, Eto M, Kano MR, et al: Induction of endothelial nitric oxide synthase, SIRT1, and catalase by statins inhibits endothelial senescence through the Akt pathway. Arterioscler Thromb Vasc Biol. 30:2205–2211. 2010. View Article : Google Scholar : PubMed/NCBI

34 

Dimitrova KR and Leitman IM: Intramyocardial transplantation of endothelial progenitor cells and erythropoietin: a new scope for the treatment of cardiovascular disease. J Surg Res. 183:550–552. 2013. View Article : Google Scholar : PubMed/NCBI

35 

Hu CH, Ke X, Chen K, Yang DY, Du ZM and Wu GF: Transplantation of human umbilical cord-derived endothelial progenitor cells promotes re-endothelialization of the injured carotid artery after balloon injury in New Zealand white rabbits. Chin Med J (Engl). 126:1480–1485. 2013.

36 

Liu P, Zhou B, Gu D, Zhang L and Han Z: Endothelial progenitor cell therapy in atherosclerosis: a double-edged sword? Ageing Res Rev. 8:83–93. 2009. View Article : Google Scholar : PubMed/NCBI

37 

Du G, Zhou L, Ghang Q and Li Z: Inhibitory effect of simvastatin on replicative senescence of endothelial progenitor cells and its mechanism. J Jilin Univ (Medicine Edition). 39:913–918. 2013.

38 

Thum T, Fraccarollo D, Galuppo P, et al: Bone marrow molecular alterations after myocardial infarction: impact on endothelial progenitor cells. Cardiovasc Res. 70:50–60. 2006. View Article : Google Scholar : PubMed/NCBI

39 

Tousoulis D, Oikonomou E, Siasos G and Stefanadis C: Statins in heart failure - with preserved and reduced ejection fraction. An update Pharmacol Ther. 141:79–91. 2014. View Article : Google Scholar : PubMed/NCBI

40 

Balakumar P, Kathuria S, Taneja G, Kalra S and Mahadevan N: Is targeting eNOS a key mechanistic insight of cardiovascular defensive potentials of statins? J Mol Cell Cardiol. 52:83–92. 2012. View Article : Google Scholar : PubMed/NCBI

41 

Xu S, Zhao Y, Yu L, Shen X, Ding F and Fu G: Rosiglitazone attenuates endothelial progenitor cell apoptosis induced by TNF-α via ERK/MAPK and NF-κB signal pathways. J Pharmacol Sci. 117:265–274. 2011.PubMed/NCBI

42 

Yuan H, Wang Z, Li L, et al: Activation of stress response gene SIRT1 by BCR-ABL promotes leukemogenesis. Blood. 119:1904–1914. 2012. View Article : Google Scholar : PubMed/NCBI

43 

Huang PS, Son JH, Abbott LC and Winzer-Serhan UH: Regulated expression of neuronal SIRT1 and related genes by aging and neuronal β2-containing nicotinic cholinergic receptors. Neuroscience. 196:189–202. 2011.PubMed/NCBI

44 

Jeong J, Juhn K, Lee H, et al: SIRT1 promotes DNA repair activity and deacetylation of Ku70. Exp Mol Med. 39:8–13. 2007. View Article : Google Scholar : PubMed/NCBI

45 

Jin Q, Yan T, Ge X, Sun C, Shi X and Zhai Q: Cytoplasm-localized SIRT1 enhances apoptosis. J Cell Physiol. 213:88–97. 2007. View Article : Google Scholar : PubMed/NCBI

46 

Kacimi R, Karliner JS, Koudssi F and Long CS: Expression and regulation of adhesion molecules in cardiac cells by cytokines: response to acute hypoxia. Circ Res. 82:576–586. 1998. View Article : Google Scholar : PubMed/NCBI

47 

Wang W, Yan C, Zhang J, et al: SIRT1 inhibits TNF-α-induced apoptosis of vascular adventitial fibroblasts partly through the deacetylation of FoxO1. Apoptosis. 18:689–701. 2013.

48 

Dvir-Ginzberg M, Gagarina V, Lee EJ, Booth R, Gabay O and Hall DJ: Tumor necrosis factor α-mediated cleavage and inactivation of SirT1 in human osteoarthritic chondrocytes. Arthritis Rheum. 63:2363–2373. 2011.

49 

Zhang HN, Li L, Gao P, et al: Involvement of the p65/RelA subunit of NF-kappaB in TNF-alpha-induced SIRT1 expression in vascular smooth muscle cells. Biochem Biophys Res Commun. 397:569–575. 2010. View Article : Google Scholar : PubMed/NCBI

50 

Yang J, Huang C, Yang J, Jiang H and Ding J: Statins attenuate high mobility group box-1 protein induced vascular endothelial activation: a key role for TLR4/NF-κB signaling pathway. Mol Cell Biochem. 345:189–195. 2010.PubMed/NCBI

51 

Ahn KS, Sethi G and Aggarwal BB: Reversal of chemoresistance and enhancement of apoptosis by statins through downregulation of the NF-κB pathway. Biochem Pharmacol. 75:907–913. 2008.PubMed/NCBI

Related Articles

Journal Cover

July 2014
Volume 34 Issue 1

Print ISSN: 1107-3756
Online ISSN:1791-244X

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
APA
Du, G., Song, Y., Zhang, T., Ma, L., Bian, N., Chen, X. ... Li, Z. (2014). Simvastatin attenuates TNF‑α‑induced apoptosis in endothelial progenitor cells via the upregulation of SIRT1. International Journal of Molecular Medicine, 34, 177-182. https://doi.org/10.3892/ijmm.2014.1740
MLA
Du, G., Song, Y., Zhang, T., Ma, L., Bian, N., Chen, X., Feng, J., Chang, Q., Li, Z."Simvastatin attenuates TNF‑α‑induced apoptosis in endothelial progenitor cells via the upregulation of SIRT1". International Journal of Molecular Medicine 34.1 (2014): 177-182.
Chicago
Du, G., Song, Y., Zhang, T., Ma, L., Bian, N., Chen, X., Feng, J., Chang, Q., Li, Z."Simvastatin attenuates TNF‑α‑induced apoptosis in endothelial progenitor cells via the upregulation of SIRT1". International Journal of Molecular Medicine 34, no. 1 (2014): 177-182. https://doi.org/10.3892/ijmm.2014.1740