Basic Research in Cardiology

, Volume 103, Issue 5, pp 398–406 | Cite as

The role of inflammatory cytokines in endothelial dysfunction

  • Cuihua ZhangEmail author


Clinical and experimental data support a link between endothelial dysfunction and inflammation. Inflammatory cytokines are important protagonists in formation of atherosclerotic plaque, eliciting effects throughout the atherosclerotic vessel. Importantly, the development of atherosclerotic lesions, regardless of the risk factor, e.g., diabetes, hypertension, obesity, is characterized by disruption in normal function of the endothelial cells. Endothelial cells, which line the internal lumen of the vasculature, are part of a complex system that regulates vasodilation and vasoconstriction, growth of vascular smooth muscle cells, inflammation, and hemostasis, maintaining a proper blood supply to tissues and regulating inflammation and coagulation. Current concepts suggest that the earliest event in atherogenesis is endothelial dysfunction, manifested by deficiencies in the production of nitric oxide (NO) and prostacyclin. The focus of this review is to summarize recent evidence showing the effects of inflammation on vascular dysfunction in ischemic-heart disease, which may prompt new directions for targeting inflammation in future therapies.


inflammation vascular dysfunction cytokines ischemic-heart disease nitric oxide vasodilation 



The Figure design was created by Dr. Xiuping Chen. Funding Sources: Support from American Heart Association Scientist Development Grant (110350047A), Pfizer Atorvastatin Research Award (2004-37) and NIH grants (RO1-HL077566 and RO1-HL085119) to Dr. Cuihua Zhang. Conflicts of Interest: None.


  1. 1.
    Azumi H, Inoue N, Takeshita SEA (1999) Expression of NADH/NAD(P)H oxidase p22phox in human coronary arteries. Circulation 100:1494–1498PubMedGoogle Scholar
  2. 2.
    Bagi Z, Koller A, Kaley G (2004) PPAR-g activation, by reducing oxidative stress, increases NO bioavailability in coronary arterioles of mice with type 2 diabetes. Am J Physiol Heart Circ Physiol 286:H742–H748PubMedCrossRefGoogle Scholar
  3. 3.
    Belosjorow S, Bolle I, Duschin A, Heusch G, Schulz R (2003) TNF-alpha antibodies are as effective as ischemic preconditioning in reducing infarct size in rabbits. Am J Physiol Heart Circ Physiol 284:H927–H930PubMedGoogle Scholar
  4. 4.
    Bose D, Leineweber K, Konorza T, Zahn A, Brocker-Preuss M, Mann K, Haude M, Erbel R, Heusch G (2007) Release of TNF-alpha during stent implantation into saphenous vein aortocoronary bypass grafts and its relation to plaque extrusion and restenosis. Am J Physiol Heart Circ Physiol 292:H2295–H2299PubMedCrossRefGoogle Scholar
  5. 5.
    Busk M, Mertz H, Espersen GT, Rasmussen K, Maeng M (2007) Effects of pentoxifylline on the vascular response to injury after angioplasty in rabbit iliac arteries. Basic Res Cardiol 17:17Google Scholar
  6. 6.
    Cai H, Harrison DG (2000) Endothelial dysfunction in cardiovascular diseases: the role of oxidant stress. Circ Res 87:840–844PubMedGoogle Scholar
  7. 7.
    Chen X, Niroomand F, Liu Z, Zankl A, Katus HA, Jahn L, Tiefenbacher CP (2006) Expression of nitric oxide related enzymes in coronary heart disease. Basic Res Cardiol 101:346–353PubMedCrossRefGoogle Scholar
  8. 8.
    Corda S, Laplace C, Vicaut E, Duranteau J (2001) Rapid reactive oxygen species production by mitochondria in endothelial cells exposed to tumor necrosis factor-alpha is mediated by ceramide. Am J Respir Cell Mol Biol 24:762–768PubMedGoogle Scholar
  9. 9.
    De Martin R, Hoeth M, Hofer-Warbinek R, Schmid JA (2000) The transcription factor NF-kappa B and the regulation of vascular cell function. Arterioscler Thromb Vasc Biol 20:E83–E88PubMedGoogle Scholar
  10. 10.
    Deisher TA, Haddix TL, Montgomery KF, Pohlman TH, Kaushansky K, Harlan JM (1993) The role of protein kinase C in the induction of VCAM-1 expression on human umbilical vein endothelial cells. FEBS Lett 331:285–290PubMedCrossRefGoogle Scholar
  11. 11.
    De Palma C, Meacci E, Perrotta C, Bruni P, Clementi E (2006) Endothelial nitric oxide synthase activation by tumor necrosis factor alpha through neutral sphingomyelinase 2, sphingosine kinase 1, and sphingosine 1 phosphate receptors: a novel pathway relevant to the pathophysiology of endothelium. Arterioscler Thromb Vasc Biol 26:99–105PubMedCrossRefGoogle Scholar
  12. 12.
    Deswal A, Petersen NJ, Feldman AM, Young JB, White BG, Mann DL (2001) Cytokines and cytokine receptors in advanced heart failure-an analysis of the cytokine database from the vesnarinone trial (VEST). Circulation 103:2055–2059PubMedGoogle Scholar
  13. 13.
    Dorge H, Schulz R, Belosjorow S, Post H, van de Sand A, Konietzka I, Frede S, Hartung T, Vinten-Johansen J, Youker KA, Entman ML, Erbel R, Heusch G (2002) Coronary microembolization: the role of TNF-alpha in contractile dysfunction. J Mol Cell Cardiol 34:51–62PubMedCrossRefGoogle Scholar
  14. 14.
    Downey JM, Omar B, Ooiwa H, McCord J (1991) Superoxide dismutase therapy for myocardial ischemia. Free Rad Res Comms 12/13:703–720CrossRefGoogle Scholar
  15. 15.
    Feng L, Matsumoto C, Schwartz A, Schmidt AM, Stern DM, Pile-Spellman J (2005) Chronic vascular inflammation in patients with type 2 diabetes: endothelial biopsy and RT-PCR analysis. Diabetes Care 28:379–384PubMedCrossRefGoogle Scholar
  16. 16.
    Fernandez-Checa JC, Kaplowitz N, Garcia-Ruiz C, Colell A, Miranda M, Mari M, Ardite E, Morales A (1997) GSH transport in mitochondria: defense against TNF-induced oxidative stress and alcohol-induced defect. Am J Physiol 273:G7–G17PubMedGoogle Scholar
  17. 17.
    Fischer P, Hilfiker-Kleiner D (2007) Survival pathways in hypertrophy and heart failure: the gp130-STAT axis. Basic Res Cardiol 102:393–411PubMedCrossRefGoogle Scholar
  18. 18.
    Gao X, Belmadani S, Picchi A, Xu X, Potter BJ, Tewari-Singh N, Capobianco S, Chilian WM, Zhang C (2007) Tumor necrosis factor alpha-induces endothelial dysfunction in leprdb mice. Circulation 115:245–254PubMedCrossRefGoogle Scholar
  19. 19.
    Gao X, Xu X, Belmadani S, Park Y, Tang Z, Feldman AM, Chilian WM, Zhang C (2007) TNF-alpha contributes to endothelial dysfunction by up-regulation arginase in I/R injury. Arterioscler Thromb Vasc Biol 27:1269–1275PubMedCrossRefGoogle Scholar
  20. 20.
    Garcia SC, Pomblum V, Gams E, Langenbach MR, Schipke JD (2007) Independency of myocardial stunning of endothelial stunning? Basic Res Cardiol 102:359–367PubMedCrossRefGoogle Scholar
  21. 21.
    Gilmont RR, Dardano A, Engle JS, Adamson BS, Welsh MJ, Li T, Remick DG, Smith DJJ, Rees RS (1996) TNF-alpha potentiates oxidant and reperfusion-induced endothelial cell injury. J Surg Res 61:175–182PubMedCrossRefGoogle Scholar
  22. 22.
    Griendling KK, Sorescu D, Ushio-Fukai M (2000) NAD(P)H oxidase: role in cardiovascular biology and disease. Circ Res 86:494–501PubMedGoogle Scholar
  23. 23.
    Gullestad L, Aass H, Fjeld JG, Wikeby L, Andreassen AK, Ihlen H, Simonsen S, Kjekshus J, Nitter-Hauge S, Ueland T, Lien E, Frøland SS, Aukrust P (2001) Immunomodulating therapy with intravenous immunoglobulin in patients with chronic heart failure. Circulation 103:220PubMedGoogle Scholar
  24. 24.
    Guzick TJ, Mussa S, Gastaldi DEA (2002) Mechanisms of increased vascular superoxide production in human diabetes mellitus. Role of NAD(P)H oxidase and endothelial nitric oxide synthase. Circulation 105:1656–1662CrossRefGoogle Scholar
  25. 25.
    Guzik TJ, West NEJ, Black EEA (2000) Vascular superoxide production by NAD(P)H oxidase: association with endothelial dysfunction and clinical risk factors. Circ Res 86:e85–e90PubMedGoogle Scholar
  26. 26.
    Kalsch T, Elmas E, Nguyen XD, Suvajac N, Kluter H, Borggrefe M, Dempfle CE (2007) Endotoxin-induced effects on platelets and monocytes in an in vivo model of inflammation. Basic Res Cardiol 102:460–466PubMedCrossRefGoogle Scholar
  27. 27.
    Kihara M, Schmelzer JD, Poduslo JF, Curran GL, Nickander KK, Low PA (1991) Aminoguanidine effects on nerve blood flow, vascular permeability, electrophysiology, and oxygen free radicals. Proc Natl Acad Sci USA 88:6107–6111PubMedCrossRefGoogle Scholar
  28. 28.
    Kolesnick R, Golde DW (1994) The sphingomyelin pathway in tumor necrosis factor and interleukin-1 signaling. Cell 77:325–328PubMedCrossRefGoogle Scholar
  29. 29.
    Li JM, Fan LM, Christie MR, Shah AM (2005) Acute tumor necrosis factor alpha signaling via NADPH oxidase in microvascular endothelial cells: role of p47phox phosphorylation and binding to TRAF4. Mol Cell Biol 25:2320–2330PubMedCrossRefGoogle Scholar
  30. 30.
    Li JM, Mullen AM, Yun S, Wientjes F, Brouns GY, Thrasher AJ, Shah AM (2002) Essential role of the NADPH oxidase subunit p47(phox) in endothelial cell superoxide production in response to phorbol ester and tumor necrosis factor-alpha. Circ Res 90:143–150PubMedCrossRefGoogle Scholar
  31. 31.
    Luscher TM, Steffel J (2007) Sweet and sour: unraveling diabetic vascular disease. Circ Res 102:9–11CrossRefGoogle Scholar
  32. 32.
    Mathias S, Pena LA, Kolesnick RN (1998) Signal transduction of stress via ceramide. Biochem J 335:465–480PubMedGoogle Scholar
  33. 33.
    Meldrum DM, Cleveland JC, Cain BS, Meng X, Harken AH (1998) Increased myocardial tumor necrosis factor-α in a crystalloid-perfused model of cardiac ischemia-reperfusion injury. Ann Thorac Surg 65:439–443PubMedCrossRefGoogle Scholar
  34. 34.
    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 151:1548–1561PubMedGoogle Scholar
  35. 35.
    Mukherjee TK, Mukhopadhyay S, Hoidal JR (2005) The role of reactive oxygen species in TNF-alpha-dependent expression of the receptor for advanced glycation end products in human umbilical vein endothelial cells. Biochim Biophys Acta 1744:213–223PubMedCrossRefGoogle Scholar
  36. 36.
    Muzaffar S, Shukla N, Angelini G, Jeremy JY (2004) Nitroaspirins and morpholinosydnonimine but not aspirin inhibit the formation of superoxide and the expression of gp91phox induced by endotoxin and cytokines in pig pulmonary artery vascular smooth muscle cells and endothelial cells. Circulation 110:1140–1147PubMedCrossRefGoogle Scholar
  37. 37.
    Pritchard KA Jr, Groszek L, Smalley DM, Sessa WC, Wu M, Villalon P, Wolin MS, Stemerman MB (1995) Native low-density lipoprotein increases endothelial cell nitric oxide synthase generation of superoxide anion. Circ Res 77:510–518PubMedGoogle Scholar
  38. 38.
    Rajagopalan S, Kurz S, Munzel T, Tarpey M, Freeman BA, Griendling KK, Harrison DG (1996) Angiotensin II-mediated hypertension in the rat increases vascular superoxide production via membrane NADH/NADPH oxidase activation. Contribution to alterations of vasomotor tone. J Clin Invest 97:1916–1923PubMedCrossRefGoogle Scholar
  39. 39.
    Rask-Madsen C, Dominguez H, Ihlemann NEA (2003) Tumor-necrosis factor-a inhibits insulin’s stimulating effect on glucose uptake and endothelium-dependent vasodilation in humans. Circ Res 203:1815–1821Google Scholar
  40. 40.
    Schmidt A, Geigenmuller S, Volker W, Buddecke E (2006) The antiatherogenic and antiinflammatory effect of HDL-associated lysosphingolipids operates via Akt → NF-kappaB signalling pathways in human vascular endothelial cells. Basic Res Cardiol 101:109–116PubMedCrossRefGoogle Scholar
  41. 41.
    Schulz R, Aker S, Belosjorow S, Heusch G (2004) TNF in ischemia/reperfusion injury and heart failure. Basic Res Cardiol 99:8–11PubMedCrossRefGoogle Scholar
  42. 42.
    Seidel M, Billert H, Kurpisz M (2006) Regulation of eNOS expression in HCAEC cell line treated with opioids and proinflammatory cytokines. Kardiol Pol 64:153–158; discussion 159–160PubMedGoogle Scholar
  43. 43.
    Shibata Y, Kume N, Arai H, Hayashida K, Inui-Hayashida A, Minami M, Mukai E, Toyohara M, Harauma A, Murayama T, Kita T, Hara S, Kamei K, Yokode M (2007) Mulberry leaf aqueous fractions inhibit TNF-alpha-induced nuclear factor kappaB (NF-kappaB) activation and lectin-like oxidized LDL receptor-1 (LOX-1) expression in vascular endothelial cells. Atherosclerosis 193:20–27PubMedCrossRefGoogle Scholar
  44. 44.
    Shu HB, Agranoff AB, Nabel EG, Leung K, Duckett CS, Neish AS, Collins T, Nabel GJ (1993) Differential regulation of vascular cell adhesion molecule 1 gene expression by specific NF-kappa B subunits in endothelial and epithelial cells. Mol Cell Biol 13:6283–6289PubMedGoogle Scholar
  45. 45.
    Skyschally A, Gres P, Hoffmann S, Haude M, Erbel R, Schulz R, Heusch G (2007) Bidirectional role of tumor necrosis factor-{alpha} in coronary microembolization: progressive contractile dysfunction vs. delayed protection against infarction. Circ Res 100:140–146PubMedCrossRefGoogle Scholar
  46. 46.
    Sorescu D, Griendling KK (2002) Reactive oxygen species, mitochondria, and NAD(P)H oxidase in the development and progression of heart failure. Congest Heart Fail 8:132–140PubMedCrossRefGoogle Scholar
  47. 47.
    Stenvinkel P (2001) Endothelial dysfunction and inflammation—is there a link? Nephrol Dial Transplant 16:1968–1971PubMedCrossRefGoogle Scholar
  48. 48.
    Sury MD, Frese-Schaper M, Muhlemann MK, Schulthess FT, Blasig IE, Tauber MG, Shaw SG, Christen S (2006) Evidence that N-acetylcysteine inhibits TNF-alpha-induced cerebrovascular endothelin-1 upregulation via inhibition of mitogen- and stress-activated protein kinase. Free Radic Biol Med 41:1372–1383PubMedCrossRefGoogle Scholar
  49. 49.
    Szmitko PE, Wang CH, Weisel RD, de Almeida JR, Anderson TJ, Verma S (2003) New markers of inflammation and endothelial cell activation: part I. Circulation 108:1917–1923PubMedCrossRefGoogle Scholar
  50. 50.
    Tan KC, Chow WS, Ai VH, Metz C, Bucala R, Lam KS (2002) Advanced glycation end products and endothelial dysfunction in type 2 diabetes. Diabetes Care 25:1055–1059PubMedCrossRefGoogle Scholar
  51. 51.
    Tanaka N, Yonekura H, Yamagishi S, Fujimori H, Yamamoto Y, Yamamoto H (2000) The receptor for advanced glycation end products is induced by the glycation products themselves and tumor necrosis factor-alpha through nuclear factor-kappa B, and by 17beta-estradiol through Sp-1 in human vascular endothelial cells. J Biol Chem 275:25781–25790PubMedCrossRefGoogle Scholar
  52. 52.
    Tanner FC, van der Loo B, Shaw S, Greutert H, Bachschmid MM, Berrozpe M, Rozenberg I, Blau N, Siebenmann R, Schmidli J, Meyer P, Luscher TF (2007) Inactivity of nitric oxide synthase gene in the atherosclerotic human carotid artery. Basic Res Cardiol 102:308–317PubMedCrossRefGoogle Scholar
  53. 53.
    Thielmann M, Dorge H, Martin C, Belosjorow S, Schwanke U, van De Sand A, Konietzka I, Buchert A, Kruger A, Schulz R, Heusch G (2002) Myocardial dysfunction with coronary microembolization: signal transduction through a sequence of nitric oxide, tumor necrosis factor-alpha, and sphingosine. Circ Res 90:807–813PubMedCrossRefGoogle Scholar
  54. 54.
    True AL, Rahman A, Malik AB (2000) Activation of NF-kappaB induced by H(2)O(2) and TNF-alpha and its effects on ICAM-1 expression in endothelial cells. Am J Physiol Lung Cell Mol Physiol 279:L302–L311PubMedGoogle Scholar
  55. 55.
    Ushio-Fukai M, Zafari AM, Fukui TEA (1996) p22phox is a critical component of the superoxide-generating NADH/NAD(P)H oxidase system and regulates angiotensin II-induced hypertrophy in vascular smooth muscle cells. J Bio Chem 277:23317–23321Google Scholar
  56. 56.
    Valencia JV, Mone M, Zhang J, Weetall M, Buxton FP, Hughes TE (2004) Divergent pathways of gene expression are activated by the RAGE ligands S100b and AGE-BSA. Diabetes 23:743–751CrossRefGoogle Scholar
  57. 57.
    Vasquez-Vivar J, Kalyanaraman B, Martasek PEA (1998) Superoxide generation by endothelial nitric oxide synthase: the influence of cofactors. Proc Natl Acad Sci USA 95:9220–9225PubMedCrossRefGoogle Scholar
  58. 58.
    Wallach D, Varfolomeev EE, Malinin NL, Goltsev YV, Kovalenko AV, Boldin MP (1999) Tumor necrosis factor receptor and Fas signaling mechanisms. Annu Rev Immunol 17:331–367PubMedCrossRefGoogle Scholar
  59. 59.
    Warnholtz A, Nickenig G, Schulz EEA (1999) Increased NADH-oxidase-mediated superoxide production in the early stages of atherosclerosis:evidence for involvement of the renin-angiotensin system. Circulation 99:2027–2033PubMedGoogle Scholar
  60. 60.
    Westermann D, Van Linthout S, Dhayat S, Dhayat N, Schmidt A, Noutsias M, Song XY, Spillmann F, Riad A, Schultheiss HP, Tschope C (2007) Tumor necrosis factor-alpha antagonism protects from myocardial inflammation and fibrosis in experimental diabetic cardiomyopathy. Basic Res Cardiol 102:500–507PubMedCrossRefGoogle Scholar
  61. 61.
    White CR, Darley-Usmar V, Berrington WREA (1996) Circulating plasma xanthine oxidase contributes to vascular dysfunction in hypercolesterolemic rabbits. Proc Natl Acad Sci USA 93:8745–8749PubMedCrossRefGoogle Scholar
  62. 62.
    Wolf G (2000) Free radical production and angitensin. Curr Hypertens Rep 2:167–173PubMedCrossRefGoogle Scholar
  63. 63.
    Xia Z, Liu M, Wu Y, Sharma V, Luo T, Ouyang J, McNeill JH (2006) N-acetylcysteine attenuates TNF-alpha-induced human vascular endothelial cell apoptosis and restores eNOS expression. Eur J Pharmacol 550:134–142PubMedCrossRefGoogle Scholar
  64. 64.
    Xu X, Gao X, Cao JM, Zhang C (2007) Anti-LOX-1 rescues endothelial function in coronary arterioles in atherosclerotic apo-E knockout mice. Arterioscler Thromb Vasc Biol 27:871–877PubMedCrossRefGoogle Scholar
  65. 65.
    Yagihashi S, Kamijo M, Baba M, Yagihashi N, Nagai K (1992) Effect of aminoguanidine on functional and structural abnormalities in peripheral nerve of STZ-induced diabetic rats. Diabetes 41:47–52PubMedCrossRefGoogle Scholar
  66. 66.
    Yudkin GS, Stehouwer CD, Emeis JJEA (1999) C-reactive protein in healthy subjects: associations with obesity, insulin resistance, and endothelial dysfunction: a potential role for cytokines originating from adipose tissue? Arterioscler Thromb Vasc Biol 19:972–978PubMedGoogle Scholar
  67. 67.
    Zhang C, Xu X, Potter BJ, Wang W, Kuo L, Michael L, Bagby GJ, Chilian WM (2006) TNF-alpha contributes to endothelial dysfunction in ischemia/reperfusion injury. Arterioscler Thromb Vasc Biol 26:475–480PubMedCrossRefGoogle Scholar
  68. 68.
    Zhang C, Hein TW, Wang W, Ren Y, Shipley RD, Kuo L (2006) Activation of JNK and xanthine oxidase by TNF-alpha impairs nitric oxide-mediated dilation of coronary arterioles. J Mol Cell Cardiol 40:247–257PubMedCrossRefGoogle Scholar
  69. 69.
    Zhang DX, Yi FX, Zou AP, Li PL (2002) Role of ceramide in TNF-α-induced impairment of endothelium-dependent vasorelation in coronary arteries. Am J Physiol Heart Circ Physiol 283:H1758–H1794Google Scholar
  70. 70.
    Zhao RZ, Chen X, Yao Q, Chen C (2005) TNF-alpha induces interleukin-8 and endothelin-1 expression in human endothelial cells with different redox pathways. Biochem Biophys Res Commun 327:985–992PubMedCrossRefGoogle Scholar

Copyright information

© Springer 2008

Authors and Affiliations

  1. 1.Depts. of Internal Medicine, Medical Pharmacology & Physiology and Nutritional SciencesUniversity of MissouriColumbiaUSA

Personalised recommendations