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Inflammation

, Volume 38, Issue 2, pp 576–583 | Cite as

Ox-LDL Upregulates CRP Expression Through the IGF2 Pathway in THP-1 Macrophages

  • Shu-Fen Li
  • Yan-Wei Hu
  • Jia-Yi Zhao
  • Xin Ma
  • Shao-Guo Wu
  • Jing-Bo Lu
  • Ya-Rong Hu
  • Yan-Chao Wang
  • Ji-Juan Gao
  • Yan-Hua Sha
  • Lei Zheng
  • Qian Wang
Article

Abstract

C-reactive protein (CRP) is an acute-phase reactant protein that not only plays a predictive role in determining atherogenesis risk but also represents an active participant in atherogenesis onset and progression. Moreover, an increasing number of studies have reported that oxidized low-density lipoprotein (Ox-LDL) plays a significant role in the initiation and progression of atherosclerosis. However, the effect and underlying mechanism of Ox-LDL on CRP expression remains unclear. THP-1 macrophages were treated with 0, 25, 50, or 100 μg/mL of Ox-LDL for 48 h, or 50 μg/mL of Ox-LDL for 0, 12, 24, and 48 h, respectively. Messenger RNA (mRNA) and protein levels were measured by real-time quantitative PCR and Western blot analysis, respectively. We found that Ox-LDL markedly increased insulin-like growth factor 2 (IGF2) and CRP mRNA and protein levels in a dose- and time-dependent manner in THP-1 macrophages. Treatment with Ox-LDL increased CRP protein expression, and this effect was completely abolished by siRNA-mediated silencing of IGF2 in THP-1 macrophages. Moreover, treatment with pcDNA3.1-IGF2 significantly enhanced CRP protein expression in Ox-LDL-stimulated THP-1 macrophages. CRP expression is upregulated by Ox-LDL through the IGF2 pathway in THP-1 macrophages.

KEY WORDS

Ox-LDL IGF2 CRP THP-1 macrophages 

Notes

Acknowledgments

The authors gratefully acknowledge financial support from the National Natural Sciences Foundation of China (grant nos. 81271905 and 81301489).

Conflict of Interest

The authors declare that they have no competing interests.

References

  1. 1.
    Moore, K.J., and I. Tabas. 2011. Macrophages in the pathogenesis of atherosclerosis. Cell 145: 341–355.PubMedCentralPubMedCrossRefGoogle Scholar
  2. 2.
    Libby, P., P.M. Ridker, and G.K. Hansson. 2011. Progress and challenges in translating the biology of atherosclerosis. Nature 473: 317–325.PubMedCrossRefGoogle Scholar
  3. 3.
    Hansson, G.K., and P. Libby. 2006. The immune response in atherosclerosis: a double-edged sword. Nature Reviews Immunology 6: 508–519.PubMedCrossRefGoogle Scholar
  4. 4.
    Mitra, S., T. Goyal, and J.L. Mehta. 2011. Oxidized LDL, LOX-1 and Atherosclerosis. Cardiovascular Drugs and Therapy 25: 419–429.PubMedCrossRefGoogle Scholar
  5. 5.
    Tabas, I. 2010. Macrophage death and defective inflammation resolution in atherosclerosis. Nature Reviews Immunology 10: 36–46.PubMedCentralPubMedCrossRefGoogle Scholar
  6. 6.
    Vicca, S., C. Hennequin, T. Nguyen-Khoa, Z.A. Massy, B. Descamps-Latscha, T.B. Drüeke, and B. Lacour. 2000. Caspase-dependent apoptosis inTHP-1 cells exposed to oxidized low-density lipoproteins. Biochemical Biophysical Research Communications 273(3): 948–954.PubMedCrossRefGoogle Scholar
  7. 7.
    Wintergerst, E.S., J. Jelk, C. Rahner, and R. Asmis. 2000. Apoptosis induced by oxidized lowdensity lipoprotein in human monocyte-derived macrophages involves CD36and activation of caspase-3. European Journal of Biochemistry 267(19): 6050–6059.PubMedCrossRefGoogle Scholar
  8. 8.
    Hunt, K.J., A. Lukanova, S. Rinaldi, E. Lundin, T. Norat, R. Palmqvist, P. Stattin, E. Riboli, G. Hallmans, and R. Kaaks. 2006. A potential inverse association between insulin-like growth factor I and hypertension in a cross-sectional study. Annals of Epidemiology 16: 563–571.PubMedCrossRefGoogle Scholar
  9. 9.
    Van Bunderen, C.C., I.C. van Nieuwpoort, N.M. van Schoor, D.J. Deeg, P. Lips, and M.L. Drent. 2010. The association of serum Insulin-like growth factor-I with mortality, cardiovascular disease and cancer in the elderly: a population-based study. Journal of Clinical Endocrinology and Metabolism 95: 4616–4624.PubMedCrossRefGoogle Scholar
  10. 10.
    LeRoith, D., and C.T. Roberts Jr. 2003. The insulin-like growth factor system and cancer. Cancer Letters 95: 127–137.CrossRefGoogle Scholar
  11. 11.
    Pollak, M.N., E.S. Schernhammer, and S.E. Hankinso. 2004. Insulin-like growth factors andneoplasia. Nature Reviews Cancer 4: 505–518.PubMedCrossRefGoogle Scholar
  12. 12.
    Singh, P., J.M. Alex, and F. Bast. 2014. Insulin receptor (IR) and insulin-like growth factor receptor 1 (IGF-1R) signaling systems: novel treatment strategies for cancer. Medical Oncology 31(1): 805.PubMedCrossRefGoogle Scholar
  13. 13.
    Kornprat, P., P. Rehak, J. Ru¨schoff, and C. Langner. 2006. Expression of IGF-I, IGF-II, and IGF-IR in gallbladder carcinoma. A systematic analysis including primary and corresponding metastatic tumours. Journal of Clinical Pathology 59: 202–206.PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    Khandwala, H.M., I.E. McCutcheon, A. Flyvbjerg, et al. 2000. The effects of insulin-like growth factors on tumorigenesis and neoplastic growth. Endocrine Reviews 21: 215–244.PubMedCrossRefGoogle Scholar
  15. 15.
    Sukhanov, S., Y. Higashi, S.Y. Shai, C. Vaughn, J. Mohler, Y. Li, Y.H. Song, J. Titterington, and P. Delafontaine. 2007. IGF-1 reduces inflammatory responses, suppresses oxidative stress, and decreases atherosclerosis progression in ApoE-deficient mice. Arteriosclerosis, Thrombosis, and Vascular Biology 27: 2684–2690.PubMedCrossRefGoogle Scholar
  16. 16.
    Yousefzadeh, G., M. Masoomi, A. Emadzadeh, A. Shahesmaeili, and M. Sheikhvatan. 2013. The association of insulin-like growth factor-1 with severity of coronary artery disease. Journal of Cardiovascular Medicine 14: 416–420.PubMedCrossRefGoogle Scholar
  17. 17.
    Doumatey, A.P., G. Chen, F.T. Ayele, J. Zhou, M. Erdos, D. Shriner, H. Huang, J. Adeleye, W. Balogun, O. Fasanmade, T. Johnson, J. Oli, G. Okafor, A. Amoah, B.A. Eghan, K. Agyenim-Boateng, J. Acheampong, C. Adebamowo, N.P. Gerry, M.F. Christman, A. Adeyemo, and C.N. Rotimi. 2012. C-reactive protein (CRP) promoter polymorphisms influence circulating CRP levels in a genome-wide association study of African Americans. Human Molecular Genetics 21(13): 3063–3072.PubMedCentralPubMedCrossRefGoogle Scholar
  18. 18.
    Clyne, B., and J.S. Olshaker. 1999. The C-reactive protein. Journal of Emergency Medicine 17: 1019–1025.PubMedCrossRefGoogle Scholar
  19. 19.
    Fox, E.R., E.J. Benjamin, D.F. Sarpong, C.N. Rotimi, J.G. Wilson, M.W. Steffes, G. Chen, A. Adeyemo, J.K. Taylor, T.E. Samdarshi, and H.A. Taylor Jr. 2008. Epidemiology, heritability, and genetic linkage of C-reactive protein in African Americans (from the Jackson Heart Study). American Journal of Cardiology 102: 835–841.PubMedCentralPubMedCrossRefGoogle Scholar
  20. 20.
    Florez, H., S. Castillo-Florez, A. Mendez, P. Casanova-Romero, C. Larreal-Urdaneta, D. Lee, and R. Goldberg. 2006. C-reactive protein is elevated in obese patients with the metabolic syndrome. Diabetes Research and Clinical Practice 71: 92–100.PubMedCrossRefGoogle Scholar
  21. 21.
    Mugabo, Y., L. Li, and G. Renier. 2010. The connection between C-reactive protein (CRP) and diabetic vasculopathy. Focus on preclinical findings. Current Diabetes Reviews 6: 27–34.PubMedCrossRefGoogle Scholar
  22. 22.
    Hu, Y.W., X. Ma, J.L. Huang, X.R. Mao, J.Y. Yang, J.Y. Zhao, S.F. Li, Y.R. Qiu, J. Yang, L. Zheng, and Q. Wang. 2013. Dihydrocapsaicin attenuates plaque formation through a PPARc/LXRa pathway in apoE−/− mice fed a high-fat/high-cholesterol diet. PLoS ONE 8(6): e66876.PubMedCentralPubMedCrossRefGoogle Scholar
  23. 23.
    Hu, Y.W., P. Zhang, J.Y. Yang, J.L. Huang, X. Ma, S.F. Li, J.Y. Zhao, Y.R. Hu, Y.C. Wang, J.J. Gao, Y.H. Sha, L. Zheng, and Q. Wang. 2014. Nur77 Decreases atherosclerosis progression in apoE−/− mice fed a high-fat/high-cholesterol diet. PLoS ONE 9(1): e87313.PubMedCentralPubMedCrossRefGoogle Scholar
  24. 24.
    Hu, Y.W., Yang, J.Y., Ma, X., Chen, Z.P., Hu, Y.R., Zhao, J.Y., Li, S.F., Qiu, Y.R., Lu, J.B., Wang, Y.C., Gao, J.J., Sha, Y.H., Zheng, L., Wang, Q. 2014. A lincRNA-DYNLRB2-2/GPR119/GLP-1R/ABCA1-dependent signal transduction pathway is essential for the regulation of cholesterol homeostasis and inflammatory reactions. Journal of Lipid Research Feb 3Google Scholar
  25. 25.
    Ruidavets, J.B., G. Luc, E. Machez, A.L. Genoux, F. Kee, D. Arveiler, P. Morange, J.V. Woodside, P. Amouyel, A. Evans, P. Ducimetière, A. Bingham, J. Ferrières, and B. Perret. 2011. Effects of insulin-like growth factor 1 in preventing acute coronary syndromes: the PRIME study. Atherosclerosis 218: 464–469.PubMedCrossRefGoogle Scholar
  26. 26.
    Hu, Y.W., X. Ma, X.X. Li, X.H. Liu, J. Xiao, Z.C. Mo, J. Xiang, D.F. Liao, and C.K. Tang. 2009. Eicosapentaenoic acid reduces ABCA1 serine phosphorylation and impairs ABCA1-dependent cholesterol efflux through cyclic AMP/protein kinase A signaling pathway in THP-1 macrophage-derived foam cells. Atherosclerosis 204: e35–e43.PubMedCrossRefGoogle Scholar
  27. 27.
    Ketelhuth, D.F., and G.K. Hansson. 2011. Cellular immunity, low-density lipoprotein and atherosclerosis: break of tolerance in the artery wall. Thrombosis and Haemostasis 106: 779–786.PubMedCrossRefGoogle Scholar
  28. 28.
    Devaraj, S., U. Singh, and I. Jialal. 2009. The evolving role of C-reactive protein in atherothrombosis. Clinical Chemistry 55(2): 229–238.PubMedCentralPubMedCrossRefGoogle Scholar
  29. 29.
    Hirschfield, G.M., and M.B. Pepys. 2003. C-reactive protein and cardiovascular disease: new insights from an old molecule. QJM 96: 793e–807e.CrossRefGoogle Scholar
  30. 30.
    Danesh, J., J.G. Wheeler, G.M. Hirschfield, S. Eda, G. Eiriksdottir, A. Rumley, G.D. Lowe, M.B. Pepys, and V. Gudnason. 2004. C-reactive protein and other circulating markers of inflammation in the prediction of coronary heart disease. New England Journal of Medicine 350: 1387–1397.PubMedCrossRefGoogle Scholar
  31. 31.
    Bautista, L.E., P. Lopez-Jaramillo, L.M. Vera, J.P. Casas, A.P. Otero, and A.I. Guaracao. 2001. Is C-reactive protein an independent risk factor for essential hypertension? Journal of Hypertension 19: 857–861.PubMedCrossRefGoogle Scholar
  32. 32.
    Grad, Etty, and H.D. Danenberg. 2013. C-reactive protein and atherothrombosis: cause or effect? Blood Reviews 27: 23–29.PubMedCrossRefGoogle Scholar
  33. 33.
    Ross, R. 1999. Atherosclerosis—an inflammatory disease. New England Journal of Medicine 340: 115–126.PubMedCrossRefGoogle Scholar
  34. 34.
    Ikonomidis, I., F. Andreotti, E. Economou, C. Stefanadis, P. Toutouzas, and P. Nihoyannopoulos. 1999. Increased proinflammatory cytokines in patients with chronic stable angina and the irreduction by aspirin. Circulation 100: 793–798.PubMedCrossRefGoogle Scholar
  35. 35.
    Estruch, M., J.L. Sánchez-Quesada, J. Ordóñez Llanos, and S. Benítez. 2013. Electronegative LDL: a circulating modified LDL with a role in inflammation. Mediators of Inflammation 2013: 181324.PubMedCentralPubMedCrossRefGoogle Scholar
  36. 36.
    Baune, B.T., M. Rothermundt, K.H. Ladwig, C. Meisinger, and K. Berger. 2011. Systemic inflammation (interleukin 6) predicts all-cause mortality in men: results from a 9-year follow-up of the MEMO study. Age (Dordrecht, Netherlands) 33: 209–217.CrossRefGoogle Scholar
  37. 37.
    Sukhanov, S., Y. Higashi, S.Y. Shai, C. Vaughn, J. Mohler, Y. Li, Y.H. Song, J. Titterington, and P. Delafontaine. 2007. IGF-1 reduces inflammatory responses, suppresses oxidative stress, and decreases atherosclerosis progression in ApoE-deficient mice. Arteriosclerosis, Thrombosis, and Vascular Biology 27: 2684–2690.PubMedCrossRefGoogle Scholar
  38. 38.
    Bergman, D., M. Halje, M. Nordin, and W. Engström. 2013. Insulin-like growth factor 2 in development and disease: a mini-review. Gerontology 59: 240–249.PubMedCrossRefGoogle Scholar
  39. 39.
    Pardina, E., R. Ferrer, J.A. Baena-Fustegueras, A. Lecube, J.M. Fort, V. Vargas, R. Catalán, and J. Peinado-Onsurbe. 2010. The relationships between IGF-1 and CRP, NO, leptin, and adiponectin during weight loss in the morbidly obese. Obesity Surgery 20: 623–632.PubMedCrossRefGoogle Scholar
  40. 40.
    Mazière, C., and J.C. Mazière. 2009. Activation of transcription factors and gene expression by oxidized low-density lipoprotein. Free Radical Biology & Medicine 46: 127–137.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Shu-Fen Li
    • 1
  • Yan-Wei Hu
    • 1
  • Jia-Yi Zhao
    • 1
  • Xin Ma
    • 2
  • Shao-Guo Wu
    • 1
  • Jing-Bo Lu
    • 3
  • Ya-Rong Hu
    • 1
  • Yan-Chao Wang
    • 1
  • Ji-Juan Gao
    • 1
  • Yan-Hua Sha
    • 1
  • Lei Zheng
    • 1
  • Qian Wang
    • 1
  1. 1.Laboratory Medicine CenterNanfang Hospital, Southern Medical UniversityGuangzhouChina
  2. 2.Department of AnesthesiologyNanfang Hospital, Southern Medical UniversityGuangzhouChina
  3. 3.Department of Vascular SurgeryNanfang Hospital, Southern Medical UniversityGuangzhouChina

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