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Mediators of Inflammation
Volume 2017 (2017), Article ID 9632846, 11 pages
https://doi.org/10.1155/2017/9632846
Review Article

Protective Effects of Methotrexate against Proatherosclerotic Cytokines: A Review of the Evidence

1Department of Clinical Pharmacology, College of Medicine and Public Health, Flinders Medical Centre, Flinders University, Adelaide, SA, Australia
2Department of Biomedical Sciences, University of Sassari, Sassari, Italy
3Quality Control Unit, University Hospital of Sassari (AOUSS), Sassari, Italy
4Rheumatology Unit, University Clinic and AOU of Cagliari, Cagliari, Italy
5Rheumatology Unit, Department of Clinical and Experimental Medicine, University Hospital of Sassari (AOUSS), Sassari, Italy

Correspondence should be addressed to Arduino A. Mangoni; ua.ude.srednilf@inognam.oniudra

Received 20 July 2017; Revised 2 November 2017; Accepted 26 November 2017; Published 21 December 2017

Academic Editor: Sandra Helena Penha Oliveira

Copyright © 2017 Arduino A. Mangoni et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. J. S. Smolen, D. Aletaha, and I. B. McInnes, “Rheumatoid arthritis,” The Lancet, vol. 388, no. 10055, pp. 2023–2038, 2016. View at Publisher · View at Google Scholar · View at Scopus
  2. A. Gonzalez, H. Maradit Kremers, C. S. Crowson et al., “The widening mortality gap between rheumatoid arthritis patients and the general population,” Arthritis & Rheumatism, vol. 56, no. 11, pp. 3583–3587, 2007. View at Publisher · View at Google Scholar · View at Scopus
  3. M. Piga, L. Casula, D. Perra et al., “Population-based analysis of hospitalizations in a West-European region revealed major changes in hospital utilization for patients with systemic lupus erythematosus over the period 2001-2012,” Lupus, vol. 25, no. 1, pp. 28–37, 2016. View at Publisher · View at Google Scholar · View at Scopus
  4. W. S. Chung, C. L. Lin, C. L. Peng et al., “Rheumatoid arthritis and risk of acute myocardial infarction–a nationwide retrospective cohort study,” International Journal of Cardiology, vol. 168, no. 5, pp. 4750–4754, 2013. View at Publisher · View at Google Scholar · View at Scopus
  5. T. H. Liou, S. W. Huang, J. W. Lin, Y. S. Chang, C. W. Wu, and H. W. Lin, “Risk of stroke in patients with rheumatism: a nationwide longitudinal population-based study,” Scientific Reports, vol. 4, p. 5110, 2014. View at Publisher · View at Google Scholar · View at Scopus
  6. L. R. Baghdadi, R. J. Woodman, E. M. Shanahan, and A. A. Mangoni, “The impact of traditional cardiovascular risk factors on cardiovascular outcomes in patients with rheumatoid arthritis: a systematic review and meta-analysis,” PLoS One, vol. 10, no. 2, article e0117952, 2015. View at Publisher · View at Google Scholar · View at Scopus
  7. K. Lauper and C. Gabay, “Cardiovascular risk in patients with rheumatoid arthritis,” Seminars in Immunopathology, vol. 39, no. 4, pp. 447–459, 2017. View at Publisher · View at Google Scholar
  8. G. Murdaca, B. M. Colombo, P. Cagnati, R. Gulli, F. Spano, and F. Puppo, “Endothelial dysfunction in rheumatic autoimmune diseases,” Atherosclerosis, vol. 224, no. 2, pp. 309–317, 2012. View at Publisher · View at Google Scholar · View at Scopus
  9. S. Cardaropoli, F. Silvagno, E. Morra, G. P. Pescarmona, and T. Todros, “Infectious and inflammatory stimuli decrease endothelial nitric oxide synthase activity in vitro,” Journal of Hypertension, vol. 21, no. 11, pp. 2103–2110, 2003. View at Publisher · View at Google Scholar · View at Scopus
  10. C. Napoli, F. de Nigris, S. Williams-Ignarro, O. Pignalosa, V. Sica, and L. J. Ignarro, “Nitric oxide and atherosclerosis: an update,” Nitric Oxide, vol. 15, no. 4, pp. 265–279, 2006. View at Publisher · View at Google Scholar · View at Scopus
  11. J. Loscalzo, “Nitric oxide insufficiency, platelet activation, and arterial thrombosis,” Circulation Research, vol. 88, no. 8, pp. 756–762, 2001. View at Publisher · View at Google Scholar
  12. R. D. Rudic and W. C. Sessa, “Nitric oxide in endothelial dysfunction and vascular remodeling: clinical correlates and experimental links,” American Journal of Human Genetics, vol. 64, no. 3, pp. 673–677, 1999. View at Publisher · View at Google Scholar · View at Scopus
  13. I. B. Wilkinson, S. S. Franklin, and J. R. Cockcroft, “Nitric oxide and the regulation of large artery stiffness: from physiology to pharmacology,” Hypertension, vol. 44, no. 2, pp. 112–116, 2004. View at Publisher · View at Google Scholar · View at Scopus
  14. Y. Haruna, Y. Morita, N. Komai et al., “Endothelial dysfunction in rat adjuvant-induced arthritis: vascular superoxide production by NAD(P)H oxidase and uncoupled endothelial nitric oxide synthase,” Arthritis & Rheumatism, vol. 54, no. 6, pp. 1847–1855, 2006. View at Publisher · View at Google Scholar · View at Scopus
  15. S. E. Abbot, W. J. Whish, C. Jennison, D. R. Blake, and C. R. Stevens, “Tumour necrosis factor α stimulated rheumatoid synovial microvascular endothelial cells exhibit increased shear rate dependent leucocyte adhesion in vitro,” Annals of the Rheumatic Diseases, vol. 58, no. 9, pp. 573–581, 1999. View at Publisher · View at Google Scholar
  16. P. Wang, S. Y. Guan, S. Z. Xu et al., “Increased carotid intima-media thickness in rheumatoid arthritis: an update meta-analysis,” Clinical Rheumatology, vol. 35, no. 2, pp. 315–323, 2016. View at Publisher · View at Google Scholar · View at Scopus
  17. M. J. Roman, R. B. Devereux, J. E. Schwartz et al., “Arterial stiffness in chronic inflammatory diseases,” Hypertension, vol. 46, no. 1, pp. 194–199, 2005. View at Publisher · View at Google Scholar · View at Scopus
  18. J. Beinsberger, J. W. Heemskerk, and J. M. Cosemans, “Chronic arthritis and cardiovascular disease: altered blood parameters give rise to a prothrombotic propensity,” Seminars in Arthritis & Rheumatism, vol. 44, no. 3, pp. 345–352, 2014. View at Publisher · View at Google Scholar · View at Scopus
  19. P. Libby, “Inflammation in atherosclerosis,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 32, no. 9, pp. 2045–2051, 2012. View at Publisher · View at Google Scholar · View at Scopus
  20. D. Tousoulis, E. Oikonomou, E. K. Economou, F. Crea, and J. C. Kaski, “Inflammatory cytokines in atherosclerosis: current therapeutic approaches,” European Heart Journal, vol. 37, no. 22, pp. 1723–1732, 2016. View at Publisher · View at Google Scholar · View at Scopus
  21. D. P. Ramji and T. S. Davies, “Cytokines in atherosclerosis: key players in all stages of disease and promising therapeutic targets,” Cytokine & Growth Factor Reviews, vol. 26, no. 6, pp. 673–685, 2015. View at Publisher · View at Google Scholar · View at Scopus
  22. P. M. Ridker, “From C-reactive protein to interleukin-6 to interleukin-1: moving upstream to identify novel targets for atheroprotection,” Circulation Research, vol. 118, no. 1, pp. 145–156, 2016. View at Publisher · View at Google Scholar · View at Scopus
  23. C. M. Boulanger, “Endothelium,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 36, no. 4, pp. e26–e31, 2016. View at Publisher · View at Google Scholar · View at Scopus
  24. M. K. Reriani, L. O. Lerman, and A. Lerman, “Endothelial function as a functional expression of cardiovascular risk factors,” Biomarkers in Medicine, vol. 4, no. 3, pp. 351–360, 2010. View at Publisher · View at Google Scholar · View at Scopus
  25. Y. Matsuzawa, T. G. Kwon, R. J. Lennon, L. O. Lerman, and A. Lerman, “Prognostic value of flow-mediated vasodilation in brachial artery and fingertip artery for cardiovascular events: a systematic review and meta-analysis,” Journal of the American Heart Association, vol. 4, no. 11, article e002270, 2015. View at Publisher · View at Google Scholar · View at Scopus
  26. Y. Xu, R. C. Arora, B. M. Hiebert et al., “Non-invasive endothelial function testing and the risk of adverse outcomes: a systematic review and meta-analysis,” European Heart Journal Cardiovascular Imaging, vol. 15, no. 7, pp. 736–746, 2014. View at Publisher · View at Google Scholar · View at Scopus
  27. R. T. Ras, M. T. Streppel, R. Draijer, and P. L. Zock, “Flow-mediated dilation and cardiovascular risk prediction: a systematic review with meta-analysis,” International Journal of Cardiology, vol. 168, no. 1, pp. 344–351, 2013. View at Publisher · View at Google Scholar · View at Scopus
  28. H. A. Jensen and J. L. Mehta, “Endothelial cell dysfunction as a novel therapeutic target in atherosclerosis,” Expert Review of Cardiovascular Therapy, vol. 14, no. 9, pp. 1021–1033, 2016. View at Publisher · View at Google Scholar · View at Scopus
  29. A. Tedgui and Z. Mallat, “Cytokines in atherosclerosis: pathogenic and regulatory pathways,” Physiological Reviews, vol. 86, no. 2, pp. 515–581, 2006. View at Publisher · View at Google Scholar · View at Scopus
  30. M. Feldmann, F. M. Brennan, and R. N. Maini, “Role of cytokines in rheumatoid arthritis,” Annual Review of Immunology, vol. 14, no. 1, pp. 397–440, 1996. View at Publisher · View at Google Scholar · View at Scopus
  31. P. Libby and P. M. Ridker, “Novel inflammatory markers of coronary risk: theory versus practice,” Circulation, vol. 100, no. 11, pp. 1148–1150, 1999. View at Publisher · View at Google Scholar
  32. K. F. Chan, M. R. Siegel, and J. M. Lenardo, “Signaling by the TNF receptor superfamily and T cell homeostasis,” Immunity, vol. 13, no. 4, pp. 419–422, 2000. View at Publisher · View at Google Scholar
  33. H. Ait-Oufella, S. Taleb, Z. Mallat, and A. Tedgui, “Recent advances on the role of cytokines in atherosclerosis,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 31, no. 5, pp. 969–979, 2011. View at Publisher · View at Google Scholar · View at Scopus
  34. K. L. MacNaul and N. I. Hutchinson, “Differential expression of iNOS and cNOS mRNA in human vascular smooth muscle cells and endothelial cells under normal and inflammatory conditions,” Biochemical and Biophysical Research Communications, vol. 196, no. 3, pp. 1330–1334, 1993. View at Publisher · View at Google Scholar · View at Scopus
  35. W. N. Nowak, J. Deng, X. Z. Ruan, and Q. Xu, “Reactive oxygen species generation and atherosclerosis,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 37, no. 5, pp. e41–e52, 2017. View at Publisher · View at Google Scholar
  36. X. Gao, S. Belmadani, A. Picchi et al., “Tumor necrosis factor-α induces endothelial dysfunction in Leprdb mice,” Circulation, vol. 115, no. 2, pp. 245–254, 2007. View at Publisher · View at Google Scholar · View at Scopus
  37. A. Picchi, X. Gao, S. Belmadani et al., “Tumor necrosis factor-α induces endothelial dysfunction in the prediabetic metabolic syndrome,” Circulation Research, vol. 99, no. 1, pp. 69–77, 2006. View at Publisher · View at Google Scholar · View at Scopus
  38. L. A. Madge and J. S. Pober, “TNF signaling in vascular endothelial cells,” Experimental and Molecular Pathology, vol. 70, no. 3, pp. 317–325, 2001. View at Publisher · View at Google Scholar · View at Scopus
  39. A. Ito, P. S. Tsao, S. Adimoolam, M. Kimoto, T. Ogawa, and J. P. Cooke, “Novel mechanism for endothelial dysfunction: dysregulation of dimethylarginine dimethylaminohydrolase,” Circulation, vol. 99, no. 24, pp. 3092–3095, 1999. View at Publisher · View at Google Scholar
  40. C. Wadham and A. A. Mangoni, “Dimethylarginine dimethylaminohydrolase regulation: a novel therapeutic target in cardiovascular disease,” Expert Opinion on Drug Metabolism & Toxicology, vol. 5, no. 3, pp. 303–319, 2009. View at Publisher · View at Google Scholar · View at Scopus
  41. P. Willeit, D. F. Freitag, J. A. Laukkanen et al., “Asymmetric dimethylarginine and cardiovascular risk: systematic review and meta-analysis of 22 prospective studies,” Journal of the American Heart Association, vol. 4, no. 6, article e001833, 2015. View at Publisher · View at Google Scholar
  42. C. Xuan, Q. W. Tian, H. Li, B. B. Zhang, G. W. He, and L. M. Lun, “Levels of asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor, and risk of coronary artery disease: a meta-analysis based on 4713 participants,” European Journal of Preventive Cardiology, vol. 23, no. 5, pp. 502–510, 2016. View at Publisher · View at Google Scholar · View at Scopus
  43. G. Cui, H. Wang, R. Li et al., “Polymorphism of tumor necrosis factor alpha (TNF-alpha) gene promoter, circulating TNF-alpha level, and cardiovascular risk factor for ischemic stroke,” Journal of Neuroinflammation, vol. 9, p. 235, 2012. View at Publisher · View at Google Scholar · View at Scopus
  44. P. M. Ridker, N. Rifai, M. Pfeffer, F. Sacks, S. Lepage, and E. Braunwald, “Elevation of tumor necrosis factor-α and increased risk of recurrent coronary events after myocardial infarction,” Circulation, vol. 101, no. 18, pp. 2149–2153, 2000. View at Publisher · View at Google Scholar
  45. C. Rios-Navarro, C. de Pablo, V. Collado-Diaz et al., “Differential effects of anti-TNF-α and anti-IL-12/23 agents on human leukocyte-endothelial cell interactions,” European Journal of Pharmacology, vol. 765, pp. 355–365, 2015. View at Publisher · View at Google Scholar · View at Scopus
  46. G. Avgerinou, D. Tousoulis, G. Siasos et al., “Anti-tumor necrosis factor alpha treatment with adalimumab improves significantly endothelial function and decreases inflammatory process in patients with chronic psoriasis,” International Journal of Cardiology, vol. 151, no. 3, pp. 382-383, 2011. View at Publisher · View at Google Scholar · View at Scopus
  47. F. R. Spinelli, M. Di Franco, A. Metere et al., “Decrease of asymmetric dimethyl arginine after anti-TNF therapy in patients with rheumatoid arthritis,” Drug Development Research, vol. 75, Supplement 1, pp. S67–S69, 2014. View at Publisher · View at Google Scholar · View at Scopus
  48. F. R. Spinelli, A. Metere, C. Barbati et al., “Effect of therapeutic inhibition of TNF on circulating endothelial progenitor cells in patients with rheumatoid arthritis,” Mediators of Inflammation, vol. 2013, Article ID 537539, 8 pages, 2013. View at Publisher · View at Google Scholar · View at Scopus
  49. M. P. Bevilacqua, J. S. Pober, M. E. Wheeler, R. S. Cotran, and M. A. Gimbrone Jr., “Interleukin 1 acts on cultured human vascular endothelium to increase the adhesion of polymorphonuclear leukocytes, monocytes, and related leukocyte cell lines,” The Journal of Clinical Investigation, vol. 76, no. 5, pp. 2003–2011, 1985. View at Publisher · View at Google Scholar
  50. M. P. Bevilacqua, J. S. Pober, G. R. Majeau, R. S. Cotran, and M. A. Gimbrone Jr, “Interleukin 1 (IL-1) induces biosynthesis and cell surface expression of procoagulant activity in human vascular endothelial cells,” The Journal of Experimental Medicine, vol. 160, no. 2, pp. 618–623, 1984. View at Publisher · View at Google Scholar
  51. U. Ikeda, M. Ikeda, T. Oohara, S. Kano, and T. Yaginuma, “Mitogenic action of interleukin-1α on vascular smooth muscle cells mediated by PDGF,” Atherosclerosis, vol. 84, no. 2-3, pp. 183–188, 1990. View at Publisher · View at Google Scholar · View at Scopus
  52. A. Nomoto, S. Mutoh, H. Hagihara, and I. Yamaguchi, “Smooth muscle cell migration induced by inflammatory cell products and its inhibition by a potent calcium antagonist, nilvadipine,” Atherosclerosis, vol. 72, no. 2-3, pp. 213–219, 1988. View at Publisher · View at Google Scholar · View at Scopus
  53. H. Shimokawa, A. Ito, Y. Fukumoto et al., “Chronic treatment with interleukin-1 beta induces coronary intimal lesions and vasospastic responses in pigs in vivo. The role of platelet-derived growth factor,” The Journal of Clinical Investigation, vol. 97, no. 3, pp. 769–776, 1996. View at Publisher · View at Google Scholar
  54. S. E. Francis, N. J. Camp, R. M. Dewberry et al., “Interleukin-1 receptor antagonist gene polymorphism and coronary artery disease,” Circulation, vol. 99, no. 7, pp. 861–866, 1999. View at Publisher · View at Google Scholar
  55. I. Ikonomidis, J. P. Lekakis, M. Nikolaou et al., “Inhibition of interleukin-1 by anakinra improves vascular and left ventricular function in patients with rheumatoid arthritis,” Circulation, vol. 117, no. 20, pp. 2662–2669, 2008. View at Publisher · View at Google Scholar · View at Scopus
  56. S. Vallejo, E. Palacios, T. Romacho, L. Villalobos, C. Peiro, and C. F. Sanchez-Ferrer, “The interleukin-1 receptor antagonist anakinra improves endothelial dysfunction in streptozotocin-induced diabetic rats,” Cardiovascular Diabetology, vol. 13, no. 1, p. 158, 2014. View at Publisher · View at Google Scholar · View at Scopus
  57. P. M. Ridker, B. M. Everett, T. Thuren et al., “Antiinflammatory therapy with canakinumab for atherosclerotic disease,” The New England Journal of Medicine, vol. 377, no. 12, pp. 1119–1131, 2017. View at Publisher · View at Google Scholar
  58. S. Wassmann, M. Stumpf, K. Strehlow et al., “Interleukin-6 induces oxidative stress and endothelial dysfunction by overexpression of the angiotensin II type 1 receptor,” Circulation Research, vol. 94, no. 4, pp. 534–541, 2004. View at Publisher · View at Google Scholar · View at Scopus
  59. E. Esteve, A. Castro, A. Lopez-Bermejo, J. Vendrell, W. Ricart, and J. M. Fernandez-Real, “Serum interleukin-6 correlates with endothelial dysfunction in healthy men independently of insulin sensitivity,” Diabetes Care, vol. 30, no. 4, pp. 939–945, 2007. View at Publisher · View at Google Scholar · View at Scopus
  60. M. Naya, T. Tsukamoto, K. Morita et al., “Plasma interleukin-6 and tumor necrosis factor-α can predict coronary endothelial dysfunction in hypertensive patients,” Hypertension Research, vol. 30, no. 6, pp. 541–548, 2007. View at Publisher · View at Google Scholar · View at Scopus
  61. H. Nawawi, N. S. Osman, R. Annuar, B. A. Khalid, and K. Yusoff, “Soluble intercellular adhesion molecule-1 and interleukin-6 levels reflect endothelial dysfunction in patients with primary hypercholesterolaemia treated with atorvastatin,” Atherosclerosis, vol. 169, no. 2, pp. 283–291, 2003. View at Publisher · View at Google Scholar · View at Scopus
  62. A. Mahmud and J. Feely, “Arterial stiffness is related to systemic inflammation in essential hypertension,” Hypertension, vol. 46, no. 5, pp. 1118–1122, 2005. View at Publisher · View at Google Scholar · View at Scopus
  63. S. Kaptoge, S. R. Seshasai, P. Gao et al., “Inflammatory cytokines and risk of coronary heart disease: new prospective study and updated meta-analysis,” European Heart Journal, vol. 35, no. 9, pp. 578–589, 2014. View at Publisher · View at Google Scholar · View at Scopus
  64. A. D. Protogerou, E. Zampeli, K. Fragiadaki, K. Stamatelopoulos, C. Papamichael, and P. P. Sfikakis, “A pilot study of endothelial dysfunction and aortic stiffness after interleukin-6 receptor inhibition in rheumatoid arthritis,” Atherosclerosis, vol. 219, no. 2, pp. 734–736, 2011. View at Publisher · View at Google Scholar · View at Scopus
  65. B. C. Bacchiega, A. B. Bacchiega, M. J. Usnayo, R. Bedirian, G. Singh, and G. D. Pinheiro, “Interleukin 6 inhibition and coronary artery disease in a high-risk population: a prospective community-based clinical study,” Journal of the American Heart Association, vol. 6, no. 3, article e005038, 2017. View at Publisher · View at Google Scholar
  66. P. Ruiz-Limon, R. Ortega, I. Arias de la Rosa et al., “Tocilizumab improves the proatherothrombotic profile of rheumatoid arthritis patients modulating endothelial dysfunction, NETosis, and inflammation,” Translational Research, vol. 183, pp. 87–103, 2017. View at Publisher · View at Google Scholar · View at Scopus
  67. A. Floris, M. Piga, A. Cauli, and A. Mathieu, “Predictors of flares in systemic lupus erythematosus: preventive therapeutic intervention based on serial anti-dsDNA antibodies assessment. Analysis of a monocentric cohort and literature review,” Autoimmunity Reviews, vol. 15, no. 7, pp. 656–663, 2016. View at Publisher · View at Google Scholar · View at Scopus
  68. J. Braun, “Methotrexate: optimizing the efficacy in rheumatoid arthritis,” Therapeutic Advances in Musculoskeletal Disease, vol. 3, no. 3, pp. 151–158, 2011. View at Publisher · View at Google Scholar · View at Scopus
  69. H. K. Choi, M. A. Hernan, J. D. Seeger, J. M. Robins, and F. Wolfe, “Methotrexate and mortality in patients with rheumatoid arthritis: a prospective study,” The Lancet, vol. 359, no. 9313, pp. 1173–1177, 2002. View at Publisher · View at Google Scholar · View at Scopus
  70. D. Krause, B. Schleusser, G. Herborn, and R. Rau, “Response to methotrexate treatment is associated with reduced mortality in patients with severe rheumatoid arthritis,” Arthritis & Rheumatism, vol. 43, no. 1, pp. 14–21, 2000. View at Publisher · View at Google Scholar
  71. M. C. Wasko, A. Dasgupta, H. Hubert, J. F. Fries, and M. M. Ward, “Propensity-adjusted association of methotrexate with overall survival in rheumatoid arthritis,” Arthritis & Rheumatism, vol. 65, no. 2, pp. 334–342, 2013. View at Publisher · View at Google Scholar · View at Scopus
  72. B. Bannwarth, F. Pehourcq, T. Schaeverbeke, and J. Dehais, “Clinical pharmacokinetics of low-dose pulse methotrexate in rheumatoid arthritis,” Clinical Pharmacokinetics, vol. 30, no. 3, pp. 194–210, 1996. View at Publisher · View at Google Scholar
  73. S. Pan, L. K. Stamp, S. B. Duffull et al., “Assessment of the relationship between methotrexate polyglutamates in red blood cells and clinical response in patients commencing methotrexate for rheumatoid arthritis,” Clinical Pharmacokinetics, vol. 53, no. 12, pp. 1161–1170, 2014. View at Publisher · View at Google Scholar · View at Scopus
  74. M. C. de Rotte, E. den Boer, P. H. de Jong et al., “Methotrexate polyglutamates in erythrocytes are associated with lower disease activity in patients with rheumatoid arthritis,” Annals of the Rheumatic Diseases, vol. 74, no. 2, pp. 408–414, 2015. View at Publisher · View at Google Scholar · View at Scopus
  75. K. Inoue and H. Yuasa, “Molecular basis for pharmacokinetics and pharmacodynamics of methotrexate in rheumatoid arthritis therapy,” Drug Metabolism and Pharmacokinetics, vol. 29, no. 1, pp. 12–19, 2014. View at Publisher · View at Google Scholar · View at Scopus
  76. G. Hasko and B. Cronstein, “Regulation of inflammation by adenosine,” Frontiers in Immunology, vol. 4, p. 85, 2013. View at Publisher · View at Google Scholar · View at Scopus
  77. B. N. Cronstein, D. Naime, and E. Ostad, “The antiinflammatory mechanism of methotrexate. Increased adenosine release at inflamed sites diminishes leukocyte accumulation in an in vivo model of inflammation,” The Journal of Clinical Investigation, vol. 92, no. 6, pp. 2675–2682, 1993. View at Publisher · View at Google Scholar
  78. D. G. Hardie, “AMP-activated protein kinase-an energy sensor that regulates all aspects of cell function,” Genes & Development, vol. 25, no. 18, pp. 1895–1908, 2011. View at Publisher · View at Google Scholar · View at Scopus
  79. L. Antonioli, R. Colucci, C. Pellegrini et al., “The AMPK enzyme-complex: from the regulation of cellular energy homeostasis to a possible new molecular target in the management of chronic inflammatory disorders,” Expert Opinion on Therapeutic Targets, vol. 20, no. 2, pp. 179–191, 2016. View at Publisher · View at Google Scholar · View at Scopus
  80. F. Boin, G. L. Erre, A. M. Posadino et al., “Oxidative stress-dependent activation of collagen synthesis is induced in human pulmonary smooth muscle cells by sera from patients with scleroderma-associated pulmonary hypertension,” Orphanet Journal of Rare Diseases, vol. 9, no. 1, p. 123, 2014. View at Publisher · View at Google Scholar · View at Scopus
  81. M. Igata, H. Motoshima, K. Tsuruzoe et al., “Adenosine monophosphate-activated protein kinase suppresses vascular smooth muscle cell proliferation through the inhibition of cell cycle progression,” Circulation Research, vol. 97, no. 8, pp. 837–844, 2005. View at Publisher · View at Google Scholar · View at Scopus
  82. Y. Ma, L. Li, Y. Shao, X. Bai, T. Bai, and X. Huang, “Methotrexate improves perivascular adipose tissue/endothelial dysfunction via activation of AMPK/eNOS pathway,” Molecular Medicine Reports, vol. 15, no. 4, pp. 2353–2359, 2017. View at Publisher · View at Google Scholar
  83. R. Micha, F. Imamura, M. Wyler von Ballmoos et al., “Systematic review and meta-analysis of methotrexate use and risk of cardiovascular disease,” The American Journal of Cardiology, vol. 108, no. 9, pp. 1362–1370, 2011. View at Publisher · View at Google Scholar · View at Scopus
  84. C. Roubille, V. Richer, T. Starnino et al., “The effects of tumour necrosis factor inhibitors, methotrexate, non-steroidal anti-inflammatory drugs and corticosteroids on cardiovascular events in rheumatoid arthritis, psoriasis and psoriatic arthritis: a systematic review and meta-analysis,” Annals of the Rheumatic Diseases, vol. 74, no. 3, pp. 480–489, 2015. View at Publisher · View at Google Scholar · View at Scopus
  85. M. Seitz, M. Zwicker, and P. Loetscher, “Effects of methotrexate on differentiation of monocytes and production of cytokine inhibitors by monocytes,” Arthritis & Rheumatism, vol. 41, no. 11, pp. 2032–2038, 1998. View at Publisher · View at Google Scholar
  86. C. K. Edwards 3rd, A. M. Bendele, L. I. Reznikov et al., “Soluble human p55 and p75 tumor necrosis factor receptors reverse spontaneous arthritis in transgenic mice expressing transmembrane tumor necrosis factor α,” Arthritis & Rheumatism, vol. 54, no. 9, pp. 2872–2885, 2006. View at Publisher · View at Google Scholar · View at Scopus
  87. F. G. Sajjadi, K. Takabayashi, A. C. Foster, R. C. Domingo, and G. S. Firestein, “Inhibition of TNF-alpha expression by adenosine: role of A3 adenosine receptors,” Journal of Immunology, vol. 156, no. 9, pp. 3435–3442, 1996. View at Google Scholar
  88. A. Bulgarelli, A. A. Martins Dias, B. Caramelli, and R. C. Maranhao, “Treatment with methotrexate inhibits atherogenesis in cholesterol-fed rabbits,” Journal of Cardiovascular Pharmacology, vol. 59, no. 4, pp. 308–314, 2012. View at Publisher · View at Google Scholar · View at Scopus
  89. C. C. Thornton, F. Al-Rashed, D. Calay et al., “Methotrexate-mediated activation of an AMPK-CREB-dependent pathway: a novel mechanism for vascular protection in chronic systemic inflammation,” Annals of the Rheumatic Diseases, vol. 75, no. 2, pp. 439–448, 2016. View at Publisher · View at Google Scholar · View at Scopus
  90. E. Yamasaki, Y. Soma, Y. Kawa, and M. Mizoguchi, “Methotrexate inhibits proliferation and regulation of the expression of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 by cultured human umbilical vein endothelial cells,” The British Journal of Dermatology, vol. 149, no. 1, pp. 30–38, 2003. View at Publisher · View at Google Scholar · View at Scopus
  91. T. J. Kalogeris, C. Baines, and R. J. Korthuis, “Adenosine prevents TNFα-induced decrease in endothelial mitochondrial mass via activation of eNOS-PGC-1α regulatory axis,” PLoS One, vol. 9, no. 6, article e98459, 2014. View at Publisher · View at Google Scholar · View at Scopus
  92. E. S. Cohen, W. R. Law, C. R. Easington et al., “Adenosine deaminase inhibition attenuates microvascular dysfunction and improves survival in sepsis,” American Journal of Respiratory and Critical Care Medicine, vol. 166, no. 1, pp. 16–20, 2002. View at Publisher · View at Google Scholar · View at Scopus
  93. C. M. Summers, A. L. Hammons, J. Arora et al., “Methotrexate modulates folate phenotype and inflammatory profile in EA.hy 926 cells,” European Journal of Pharmacology, vol. 732, pp. 60–67, 2014. View at Publisher · View at Google Scholar · View at Scopus
  94. J. Li, Y. Wang, Y. Wang et al., “Pharmacological activation of AMPK prevents Drp1-mediated mitochondrial fission and alleviates endoplasmic reticulum stress-associated endothelial dysfunction,” Journal of Molecular and Cellular Cardiology, vol. 86, pp. 62–74, 2015. View at Publisher · View at Google Scholar · View at Scopus
  95. X. Hou and F. Pei, “Estradiol inhibits cytokine-induced expression of VCAM-1 and ICAM-1 in cultured human endothelial cells via AMPK/PPARα activation,” Cell Biochemistry and Biophysics, vol. 72, no. 3, pp. 709–717, 2015. View at Publisher · View at Google Scholar · View at Scopus
  96. A. Quan, Y. Pan, K. K. Singh et al., “Cardiovascular inflammation is reduced with methotrexate in diabetes,” Molecular and Cellular Biochemistry, vol. 432, no. 1-2, pp. 159–167, 2017. View at Publisher · View at Google Scholar
  97. S. M. Hassanian, P. Dinarvand, and A. R. Rezaie, “Adenosine regulates the proinflammatory signaling function of thrombin in endothelial cells,” Journal of Cellular Physiology, vol. 229, no. 9, pp. 1292–1300, 2014. View at Publisher · View at Google Scholar · View at Scopus
  98. M. G. Bouma, F. A. van den Wildenberg, and W. A. Buurman, “Adenosine inhibits cytokine release and expression of adhesion molecules by activated human endothelial cells,” The American Journal of Physiology, vol. 270, 2 Part 1, pp. C522–C529, 1996. View at Google Scholar
  99. J. C. Shryock and L. Belardinelli, “Adenosine and adenosine receptors in the cardiovascular system: biochemistry, physiology, and pharmacology,” The American Journal of Cardiology, vol. 79, Supplement 1, no. 12, pp. 2–10, 1997. View at Publisher · View at Google Scholar
  100. R. A. Olsson and J. D. Pearson, “Cardiovascular purinoceptors,” Physiological Reviews, vol. 70, no. 3, pp. 761–845, 1990. View at Google Scholar
  101. L. Stella, V. de Novellis, I. Marabese et al., “The role of A3 adenosine receptors in central regulation of arterial blood pressure,” British Journal of Pharmacology, vol. 125, no. 3, pp. 437–440, 1998. View at Publisher · View at Google Scholar · View at Scopus
  102. M. Koupenova, H. Johnston-Cox, and K. Ravid, “Regulation of atherosclerosis and associated risk factors by adenosine and adenosine receptors,” Current Atherosclerosis Reports, vol. 14, no. 5, pp. 460–468, 2012. View at Publisher · View at Google Scholar · View at Scopus
  103. K. Varani, F. Portaluppi, S. Merighi, E. Ongini, L. Belardinelli, and P. A. Borea, “Caffeine alters A2A adenosine receptors and their function in human platelets,” Circulation, vol. 99, no. 19, pp. 2499–2502, 1999. View at Publisher · View at Google Scholar
  104. L. Antonioli, C. Blandizzi, B. Csoka, P. Pacher, and G. Hasko, “Adenosine signalling in diabetes mellitus--pathophysiology and therapeutic considerations,” Nature Reviews. Endocrinology, vol. 11, no. 4, pp. 228–241, 2015. View at Publisher · View at Google Scholar · View at Scopus
  105. D. Li, D. Wang, Y. Wang, W. Ling, X. Feng, and M. Xia, “Adenosine monophosphate-activated protein kinase induces cholesterol efflux from macrophage-derived foam cells and alleviates atherosclerosis in apolipoprotein E-deficient mice,” The Journal of Biological Chemistry, vol. 285, no. 43, pp. 33499–33509, 2010. View at Publisher · View at Google Scholar · View at Scopus
  106. Z. Chen, I. C. Peng, W. Sun et al., “AMP-activated protein kinase functionally phosphorylates endothelial nitric oxide synthase Ser633,” Circulation Research, vol. 104, no. 4, pp. 496–505, 2009. View at Publisher · View at Google Scholar · View at Scopus
  107. F. Goirand, M. Solar, Y. Athea et al., “Activation of AMP kinase α1 subunit induces aortic vasorelaxation in mice,” The Journal of Physiology, vol. 581, no. 3, pp. 1163–1171, 2007. View at Publisher · View at Google Scholar · View at Scopus
  108. D. Nagata, R. Takeda, M. Sata et al., “AMP-activated protein kinase inhibits angiotensin II-stimulated vascular smooth muscle cell proliferation,” Circulation, vol. 110, no. 4, pp. 444–451, 2004. View at Publisher · View at Google Scholar · View at Scopus
  109. R. J. Ford, S. R. Teschke, E. B. Reid, K. K. Durham, J. T. Kroetsch, and J. W. Rush, “AMP-activated protein kinase activator AICAR acutely lowers blood pressure and relaxes isolated resistance arteries of hypertensive rats,” Journal of Hypertension, vol. 30, no. 4, pp. 725–733, 2012. View at Publisher · View at Google Scholar · View at Scopus
  110. E. S. Buhl, N. Jessen, R. Pold et al., “Long-term AICAR administration reduces metabolic disturbances and lowers blood pressure in rats displaying features of the insulin resistance syndrome,” Diabetes, vol. 51, no. 7, pp. 2199–2206, 2002. View at Publisher · View at Google Scholar
  111. N. Wu, B. Zheng, A. Shaywitz et al., “AMPK-dependent degradation of TXNIP upon energy stress leads to enhanced glucose uptake via GLUT1,” Molecular Cell, vol. 49, no. 6, pp. 1167–1175, 2013. View at Publisher · View at Google Scholar · View at Scopus
  112. S. L. McGee, B. J. van Denderen, K. F. Howlett et al., “AMP-activated protein kinase regulates GLUT4 transcription by phosphorylating histone deacetylase 5,” Diabetes, vol. 57, no. 4, pp. 860–867, 2008. View at Publisher · View at Google Scholar · View at Scopus
  113. A. S. Marsin, L. Bertrand, M. H. Rider et al., “Phosphorylation and activation of heart PFK-2 by AMPK has a role in the stimulation of glycolysis during ischaemia,” Current Biology, vol. 10, no. 20, pp. 1247–1255, 2000. View at Publisher · View at Google Scholar · View at Scopus
  114. A. S. Marsin, C. Bouzin, L. Bertrand, and L. Hue, “The stimulation of glycolysis by hypoxia in activated monocytes is mediated by AMP-activated protein kinase and inducible 6-phosphofructo-2-kinase,” The Journal of Biological Chemistry, vol. 277, no. 34, pp. 30778–30783, 2002. View at Publisher · View at Google Scholar · View at Scopus
  115. Z. Xie, J. Zhang, J. Wu, B. Viollet, and M. H. Zou, “Upregulation of mitochondrial uncoupling protein-2 by the AMP-activated protein kinase in endothelial cells attenuates oxidative stress in diabetes,” Diabetes, vol. 57, no. 12, pp. 3222–3230, 2008. View at Publisher · View at Google Scholar · View at Scopus
  116. X. N. Li, J. Song, L. Zhang et al., “Activation of the AMPK-FOXO3 pathway reduces fatty acid-induced increase in intracellular reactive oxygen species by upregulating thioredoxin,” Diabetes, vol. 58, no. 10, pp. 2246–2257, 2009. View at Publisher · View at Google Scholar · View at Scopus
  117. S. Hirata, T. Matsubara, R. Saura, H. Tateishi, and K. Hirohata, “Inhibition of in vitro vascular endothelial cell proliferation and in vivo neovascularization by low-dose methotrexate,” Arthritis & Rheumatism, vol. 32, no. 9, pp. 1065–1073, 1989. View at Publisher · View at Google Scholar · View at Scopus
  118. T. Annussek, T. Szuwart, J. Kleinheinz, C. Koiky, and K. Wermker, “In vitro inhibition of HUVECs by low dose methotrexate - insights into oral adverse events,” Head & Face Medicine, vol. 10, no. 1, p. 19, 2014. View at Publisher · View at Google Scholar · View at Scopus
  119. L. Gao, K. Chalupsky, E. Stefani, and H. Cai, “Mechanistic insights into folic acid-dependent vascular protection: dihydrofolate reductase (DHFR)-mediated reduction in oxidant stress in endothelial cells and angiotensin II-infused mice: a novel HPLC-based fluorescent assay for DHFR activity,” Journal of Molecular and Cellular Cardiology, vol. 47, no. 6, pp. 752–760, 2009. View at Publisher · View at Google Scholar · View at Scopus
  120. J. L. Pastrana, X. Sha, A. Virtue et al., “Regulatory T cells and atherosclerosis,” Journal of Clinical & Experimental Cardiology, vol. 1, Supplement 12, p. 2, 2013. View at Publisher · View at Google Scholar
  121. B. M. Everett, A. D. Pradhan, D. H. Solomon et al., “Rationale and design of the cardiovascular inflammation reduction trial: a test of the inflammatory hypothesis of atherothrombosis,” American Heart Journal, vol. 166, no. 2, pp. 199–207.e15, 2013. View at Publisher · View at Google Scholar · View at Scopus