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Chronic etanercept treatment prevents the development of hypertension in fructose-fed rats

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Abstract

The purpose of this study was to investigate the effect of chronic treatment with etanercept (a soluble recombinant fusion protein consisting of the extracellular ligand-binding domain of tumor necrosis factor receptor type 2) on the development of hypertension in fructose-fed rats (FFR). High fructose feeding and treatment with etanercept (0.3 mg/kg, three times per week) was initiated simultaneously in male Wistar rats. Systolic blood pressure, fasted plasma parameters, insulin sensitivity, vascular reactivity, plasma angiotensin II (Ang II), and norepinephrine were determined following 9 weeks of treatment. FFR exhibited insulin resistance, hyperinsulinemia, hypertriglyceridemia, endothelial dysfunction, and hypertension. Treatment with etanercept prevented the rise in blood pressure without affecting insulin levels, insulin sensitivity, triglycerides, or Ang II levels in FFR. Etanercept treatment improved acetylcholine-induced relaxation and normalized endothelial nitric oxide synthase expression in aortas from FFR. The results of this study suggest that treatment with etanercept prevented the development of hypertension by improving vascular function and restoring endothelial nitric oxide synthase expression in FFR.

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References

  1. Reaven GM (1988) Banting lecture 1988. Role of insulin resistance in human disease. Diabetes 37:1595–1607. doi:10.2337/diabetes.37.12.1595

    Article  PubMed  CAS  Google Scholar 

  2. Ginsberg HN (2000) Insulin resistance and cardiovascular disease. J Clin Invest 106:453–458. doi:10.1172/JCI10762

    Article  PubMed  CAS  Google Scholar 

  3. Pickup JC, Crook MA (1998) Is type II diabetes mellitus a disease of the innate immune system? Diabetologia 41:1241–1248. doi:10.1007/s001250051058

    Article  PubMed  CAS  Google Scholar 

  4. Festa A, D’Agostino R Jr, Howard G, Mykkanen L, Tracy RP, Haffner SM (2000) Chronic subclinical inflammation as part of the insulin resistance syndrome: the Insulin Resistance Atherosclerosis Study (IRAS). Circulation 102:42–47

    PubMed  CAS  Google Scholar 

  5. Pickup JC, Mattock MB, Chusney GD, Burt D (1997) NIDDM as a disease of the innate immune system: association of acute-phase reactants and interleukin-6 with metabolic syndrome X. Diabetologia 40:1286–1292. doi:10.1007/s001250050822

    Article  PubMed  CAS  Google Scholar 

  6. Frohlich M, Imhof A, Berg G, Hutchinson WL, Pepys MB, Boeing H, Muche R, Brenner H, Koenig W (2000) Association between C-reactive protein and features of the metabolic syndrome: a population-based study. Diabetes Care 23:1835–1839. doi:10.2337/diacare.23.12.1835

    Article  PubMed  CAS  Google Scholar 

  7. Moller DE (2000) Potential role of TNF-alpha in the pathogenesis of insulin resistance and type 2 diabetes. Trends Endocrinol Metab 11:212–217. doi:10.1016/S1043-2760(00)00272-1

    Article  PubMed  CAS  Google Scholar 

  8. Borst SE (2004) The role of TNF-alpha in insulin resistance. Endocrine 23:177–182. doi:10.1385/ENDO:23:2-3:177

    Article  PubMed  CAS  Google Scholar 

  9. Tracey D, Klareskog L, Sasso EH, Salfeld JG, Tak PP (2008) Tumor necrosis factor antagonist mechanisms of action: a comprehensive review. Pharmacol Ther 117:244–279. doi:10.1016/j.pharmthera.2007.10.001

    Article  PubMed  CAS  Google Scholar 

  10. Hayden MS, Ghosh S (2004) Signaling to NF-kappaB. Genes Dev 18:2195–2224. doi:10.1101/gad.1228704

    Article  PubMed  CAS  Google Scholar 

  11. Perkins ND (2007) Integrating cell-signalling pathways with NF-kappaB and IKK function. Nat Rev Mol Cell Biol 8:49–62. doi:10.1038/nrm2083

    Article  PubMed  CAS  Google Scholar 

  12. Hotamisligil GS, Shargill NS, Spiegelman BM (1993) Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science 259:87–91. doi:10.1126/science.7678183

    Article  PubMed  CAS  Google Scholar 

  13. Hofmann C, Lorenz K, Braithwaite SS, Colca JR, Palazuk BJ, Hotamisligil GS, Spiegelman BM (1994) Altered gene expression for tumor necrosis factor-alpha and its receptors during drug and dietary modulation of insulin resistance. Endocrinology 134:264–270. doi:10.1210/en.134.1.264

    Article  PubMed  CAS  Google Scholar 

  14. Hotamisligil GS, Murray DL, Choy LN, Spiegelman BM (1994) Tumor necrosis factor alpha inhibits signaling from the insulin receptor. Proc Natl Acad Sci USA 91:4854–4858. doi:10.1073/pnas.91.11.4854

    Article  PubMed  CAS  Google Scholar 

  15. Uysal KT, Wiesbrock SM, Marino MW, Hotamisligil GS (1997) Protection from obesity-induced insulin resistance in mice lacking TNF-alpha function. Nature 389:610–614. doi:10.1038/39335

    Article  PubMed  CAS  Google Scholar 

  16. Cheung AT, Ree D, Kolls JK, Fuselier J, Coy DH, Bryer-Ash M (1998) An in vivo model for elucidation of the mechanism of tumor necrosis factor-alpha (TNF-alpha)-induced insulin resistance: evidence for differential regulation of insulin signaling by TNF-alpha. Endocrinology 139:4928–4935. doi:10.1210/en.139.12.4928

    Article  PubMed  CAS  Google Scholar 

  17. Zinman B, Hanley AJ, Harris SB, Kwan J, Fantus IG (1999) Circulating tumor necrosis factor-alpha concentrations in a native Canadian population with high rates of type 2 diabetes mellitus. J Clin Endocrinol Metab 84:272–278. doi:10.1210/jc.84.1.272

    Article  PubMed  CAS  Google Scholar 

  18. Ito H, Ohshima A, Tsuzuki M, Ohto N, Takao K, Hijii C, Yanagawa M, Ogasawara M, Nishioka K (2001) Association of serum tumour necrosis factor-alpha with serum low-density lipoprotein-cholesterol and blood pressure in apparently healthy Japanese women. Clin Exp Pharmacol Physiol 28:188–192. doi:10.1046/j.1440-1681.2001.03429.x

    Article  PubMed  CAS  Google Scholar 

  19. Bautista LE, Vera LM, Arenas IA, Gamarra G (2005) Independent association between inflammatory markers (C-reactive protein, interleukin-6, and TNF-alpha) and essential hypertension. J Hum Hypertens 19:149–154. doi:10.1038/sj.jhh.1001785

    Article  PubMed  CAS  Google Scholar 

  20. Togashi N, Ura N, Higashiura K, Murakami H, Shimamoto K (2002) Effect of TNF-alpha-converting enzyme inhibitor on insulin resistance in fructose-fed rats. Hypertension 39:578–580. doi:10.1161/hy0202.103290

    Article  PubMed  CAS  Google Scholar 

  21. DeFronzo RA (1992) Insulin resistance, hyperinsulinemia, and coronary artery disease: a complex metabolic web. J Cardiovasc Pharmacol 20(Suppl 11):S1–S16. doi:10.1097/00005344-199200111-00002

    Article  PubMed  Google Scholar 

  22. Bhanot S, McNeill JH (1996) Insulin and hypertension: a causal relationship? Cardiovasc Res 31:212–221

    PubMed  CAS  Google Scholar 

  23. Antonipillai I, Wang Y, Horton R (1990) Tumor necrosis factor and interleukin-1 may regulate renin secretion. Endocrinology 126:273–278

    Article  PubMed  CAS  Google Scholar 

  24. Brasier AR, Li J, Wimbish KA (1996) Tumor necrosis factor activates angiotensinogen gene expression by the Rel A transactivator. Hypertension 27:1009–1017

    PubMed  CAS  Google Scholar 

  25. Gurantz D, Cowling RT, Villarreal FJ, Greenberg BH (1999) Tumor necrosis factor-alpha upregulates angiotensin II type 1 receptors on cardiac fibroblasts. Circ Res 85:272–279

    PubMed  CAS  Google Scholar 

  26. Joussen AM, Poulaki V, Mitsiades N, Kirchhof B, Koizumi K, Dohmen S, Adamis AP (2002) Nonsteroidal anti-inflammatory drugs prevent early diabetic retinopathy via TNF-alpha suppression. FASEB J 16:438–440

    PubMed  CAS  Google Scholar 

  27. Arenas IA, Armstrong SJ, Xu Y, Davidge ST (2005) Chronic tumor necrosis factor-alpha inhibition enhances NO modulation of vascular function in estrogen-deficient rats. Hypertension 46:76–81. doi:10.1161/01.HYP.0000168925.98963.ef

    Article  PubMed  CAS  Google Scholar 

  28. Arenas IA, Armstrong SJ, Xu Y, Davidge ST (2006) Tumor necrosis factor-alpha and vascular angiotensin II in estrogen-deficient rats. Hypertension 48:497–503. doi:10.1161/01.HYP.0000235865.03528.f1

    Article  PubMed  CAS  Google Scholar 

  29. Bunag RD (1973) Validation in awake rats of a tail-cuff method for measuring systolic pressure. J Appl Physiol 34:279–282

    PubMed  CAS  Google Scholar 

  30. Hwang IS, Ho H, Hoffman BB, Reaven GM (1987) Fructose-induced insulin resistance and hypertension in rats. Hypertension 10:512–516

    PubMed  CAS  Google Scholar 

  31. Matsuda M, DeFronzo RA (1999) Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulin clamp. Diabetes Care 22:1462–1470. doi:10.2337/diacare.22.9.1462

    Article  PubMed  CAS  Google Scholar 

  32. Verma S, Bhanot S, Yao L, McNeill JH (1996) Defective endothelium-dependent relaxation in fructose-hypertensive rats. Am J Hypertens 9:370–376. doi:10.1016/0895-7061(95)00392-4

    Article  PubMed  CAS  Google Scholar 

  33. Verma S, Bhanot S, McNeill JH (1996) Decreased vascular reactivity in metformin-treated fructose-hypertensive rats. Metabolism 45:1053–1055. doi:10.1016/S0026-0495(96)90000-1

    Article  PubMed  CAS  Google Scholar 

  34. Eissner G, Kirchner S, Lindner H, Kolch W, Janosch P, Grell M, Scheurich P, Andreesen R, Holler E (2000) Reverse signaling through transmembrane TNF confers resistance to lipopolysaccharide in human monocytes and macrophages. J Immunol 164:6193–6198

    PubMed  CAS  Google Scholar 

  35. Bernstein LE, Berry J, Kim S, Canavan B, Grinspoon SK (2006) Effects of etanercept in patients with the metabolic syndrome. Arch Intern Med 166:902–908. doi:10.1001/archinte.166.8.902

    Article  PubMed  CAS  Google Scholar 

  36. Lo J, Bernstein LE, Canavan B, Torriani M, Jackson MB, Ahima RS, Grinspoon SK (2007) Effects of TNF-alpha neutralization on adipocytokines and skeletal muscle adiposity in the metabolic syndrome. Am J Physiol Endocrinol Metab 293:E102–E109. doi:10.1152/ajpendo.00089.2007

    Article  PubMed  CAS  Google Scholar 

  37. Ofei F, Hurel S, Newkirk J, Sopwith M, Taylor R (1996) Effects of an engineered human anti-TNF-alpha antibody (CDP571) on insulin sensitivity and glycemic control in patients with NIDDM. Diabetes 45:881–885. doi:10.2337/diabetes.45.7.881

    Article  PubMed  Google Scholar 

  38. Paquot N, Castillo MJ, Lefebvre PJ, Scheen AJ (2000) No increased insulin sensitivity after a single intravenous administration of a recombinant human tumor necrosis factor receptor: Fc fusion protein in obese insulin-resistant patients. J Clin Endocrinol Metab 85:1316–1319. doi:10.1210/jc.85.3.1316

    Article  PubMed  CAS  Google Scholar 

  39. Dominguez H, Storgaard H, Rask-Madsen C, Steffen Hermann T, Ihlemann N, Baunbjerg Nielsen D, Spohr C, Kober L, Vaag A, Torp-Pedersen C (2005) Metabolic and vascular effects of tumor necrosis factor-alpha blockade with etanercept in obese patients with type 2 diabetes. J Vasc Res 42:517–525. doi:10.1159/000088261

    Article  PubMed  CAS  Google Scholar 

  40. Scallon B, Cai A, Solowski N, Rosenberg A, Song XY, Shealy D, Wagner C (2002) Binding and functional comparisons of two types of tumor necrosis factor antagonists. J Pharmacol Exp Ther 301:418–426. doi:10.1124/jpet.301.2.418

    Article  PubMed  CAS  Google Scholar 

  41. Tsimberidou AM, Waddelow T, Kantarjian HM, Albitar M, Giles FJ (2003) Pilot study of recombinant human soluble tumor necrosis factor (TNF) receptor (p75) fusion protein (TNFR:Fc; Enbrel) in patients with refractory multiple myeloma: increase in plasma TNF alpha levels during treatment. Leuk Res 27:375–380. doi:10.1016/S0145-2126(02)00082-6

    Article  PubMed  CAS  Google Scholar 

  42. Madhusudan S, Foster M, Muthuramalingam SR, Braybrooke JP, Wilner S, Kaur K, Han C, Hoare S, Balkwill F, Talbot DC, Ganesan TS, Harris AL (2004) A phase II study of etanercept (Enbrel), a tumor necrosis factor alpha inhibitor in patients with metastatic breast cancer. Clin Cancer Res 10:6528–6534. doi:10.1158/1078-0432.CCR-04-0730

    Article  PubMed  CAS  Google Scholar 

  43. Nowlan ML, Drewe E, Bulsara H, Esposito N, Robins RA, Tighe PJ, Powell RJ, Todd I (2006) Systemic cytokine levels and the effects of etanercept in TNF receptor-associated periodic syndrome (TRAPS) involving a C33Y mutation in TNFRSF1A. Rheumatology (Oxford) 45:31–37. doi:10.1093/rheumatology/kei090

    Article  CAS  Google Scholar 

  44. Mohler KM, Torrance DS, Smith CA, Goodwin RG, Stremler KE, Fung VP, Madani H, Widmer MB (1993) Soluble tumor necrosis factor (TNF) receptors are effective therapeutic agents in lethal endotoxemia and function simultaneously as both TNF carriers and TNF antagonists. J Immunol 151:1548–1561

    PubMed  CAS  Google Scholar 

  45. Evans TJ, Moyes D, Carpenter A, Martin R, Loetscher H, Lesslauer W, Cohen J (1994) Protective effect of 55- but not 75-kD soluble tumor necrosis factor receptor-immunoglobulin G fusion proteins in an animal model of gram-negative sepsis. J Exp Med 180:2173–2179. doi:10.1084/jem.180.6.2173

    Article  PubMed  CAS  Google Scholar 

  46. Eason JD, Pascual M, Wee S, Farrell M, Phelan J, Boskovic S, Blosch C, Mohler KM, Cosimi AB (1996) Evaluation of recombinant human soluble dimeric tumor necrosis factor receptor for prevention of OKT3-associated acute clinical syndrome. Transplantation 61:224–228. doi:10.1097/00007890-199601270-00011

    Article  PubMed  CAS  Google Scholar 

  47. Arenas IA, Xu Y, Davidge ST (2006) Age-associated impairment in vasorelaxation to fluid shear stress in the female vasculature is improved by TNF-alpha antagonism. Am J Physiol Heart Circ Physiol 290:H1259–H1263. doi:10.1152/ajpheart.00990.2005

    Article  PubMed  CAS  Google Scholar 

  48. Csiszar A, Labinskyy N, Smith K, Rivera A, Orosz Z, Ungvari Z (2007) Vasculoprotective effects of anti-tumor necrosis factor-alpha treatment in aging. Am J Pathol 170:388–398. doi:10.2353/ajpath.2007.060708

    Article  PubMed  CAS  Google Scholar 

  49. Fichtlscherer S, Rossig L, Breuer S, Vasa M, Dimmeler S, Zeiher AM (2001) Tumor necrosis factor antagonism with etanercept improves systemic endothelial vasoreactivity in patients with advanced heart failure. Circulation 104:3023–3025. doi:10.1161/hc5001.101749

    Article  PubMed  CAS  Google Scholar 

  50. Picchi A, Gao X, Belmadani S, Potter BJ, Focardi M, Chilian WM, Zhang C (2006) Tumor necrosis factor-alpha induces endothelial dysfunction in the prediabetic metabolic syndrome. Circ Res 99:69–77. doi:10.1161/01.RES.0000229685.37402.80

    Article  PubMed  CAS  Google Scholar 

  51. Delbosc S, Paizanis E, Magous R, Araiz C, Dimo T, Cristol JP, Cros G, Azay J (2005) Involvement of oxidative stress and NADPH oxidase activation in the development of cardiovascular complications in a model of insulin resistance, the fructose-fed rat. Atherosclerosis 179:43–49. doi:10.1016/j.atherosclerosis.2004.10.018

    Article  PubMed  CAS  Google Scholar 

  52. Song D, Hutchings S, Pang CC (2005) Chronic N-acetylcysteine prevents fructose-induced insulin resistance and hypertension in rats. Eur J Pharmacol 508:205–210. doi:10.1016/j.ejphar.2004.12.018

    Article  PubMed  CAS  Google Scholar 

  53. Guzik TJ, Hoch NE, Brown KA, McCann LA, Rahman A, Dikalov S, Goronzy J, Weyand C, Harrison DG (2007) Role of the T cell in the genesis of angiotensin II induced hypertension and vascular dysfunction. J Exp Med 204:2449–2460. doi:10.1084/jem.20070657

    Article  PubMed  CAS  Google Scholar 

  54. Si X, Webb RC, Richey JM (1999) Bezafibrate, an anti-hypertriglyceridemic drug, attenuates vascular hyperresponsiveness and elevated blood pressure in fructose-induced hypertensive rats. Can J Physiol Pharmacol 77:755–762. doi:10.1139/cjpp-77-10-755

    Article  PubMed  CAS  Google Scholar 

  55. Navarro-Cid J, Maeso R, Perez-Vizcaino F, Cachofeiro V, Ruilope LM, Tamargo J, Lahera V (1995) Effects of losartan on blood pressure, metabolic alterations, and vascular reactivity in the fructose-induced hypertensive rat. Hypertension 26:1074–1078

    PubMed  CAS  Google Scholar 

  56. Chen S, Noguchi Y, Izumida T, Tatebe J, Katayama S (1996) A comparison of the hypotensive and hypoglycaemic actions of an angiotensin converting enzyme inhibitor, an AT1a antagonist and troglitazone. J Hypertens 14:1325–1330. doi:10.1097/00004872-199611000-00011

    Article  PubMed  CAS  Google Scholar 

  57. Tran LT, Macleod KM, McNeill JH (2009) Endothelin-1 modulates angiotensin II in the development of hypertension in fructose-fed rats. Mol Cell Biochem 325:89–97

    Article  PubMed  CAS  Google Scholar 

  58. Galipeau D, Arikawa E, Sekirov I, McNeill JH (2001) Chronic thromboxane synthase inhibition prevents fructose-induced hypertension. Hypertension 38:872–876

    PubMed  CAS  Google Scholar 

  59. Galipeau D, Verma S, McNeill JH (2002) Female rats are protected against fructose-induced changes in metabolism and blood pressure. Am J Physiol Heart Circ Physiol 283:H2478–H2484

    PubMed  CAS  Google Scholar 

  60. Fujioka Y, Masai M, Tsuboi S, Okumura T, Morimoto S, Tsujino T, Ohyanagi M, Iwasaki T (2003) Troglitazone reduces activity of the Na+/H+ exchanger in fructose-fed borderline hypertensive rats. Hypertens Res 26:111–116. doi:10.1291/hypres.26.111

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported by the Heart and Stroke Foundation of British Columbia and Yukon. LTT was the recipient of a Graduate Research Scholarship in Pharmacy from the Health Research Foundation of Canada’s Research-Based Pharmaceutical Companies and the Canadian Institute for Health Research and a Pacific Century Graduate Scholarship from the University of British Columbia.

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  1. Division of Pharmacology & Toxicology, Faculty of Pharmaceutical Sciences, University of British Columbia, 2146 East Mall, Vancouver, BC, V6T 1Z3, Canada

    Linda T. Tran, Kathleen M. MacLeod & John H. McNeill

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Tran, L.T., MacLeod, K.M. & McNeill, J.H. Chronic etanercept treatment prevents the development of hypertension in fructose-fed rats. Mol Cell Biochem 330, 219–228 (2009). https://doi.org/10.1007/s11010-009-0136-z

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