Managing heart disease mechanisms of cardiovascular complications in diabetes and potential new pharmacological therapies

European Heart Journal, Supplement

Volumn 5, Issue B, 2003, Pages

  He, Z ^a   Rask Madsen, C ^a   King, G L ^a  

^a JOSLIN DIABETES CENTER   (United States)

Author keywords

Cardiovascular complications; Diabetes; Hyperglycaemia; Insulin resistance; Therapy

Indexed keywords

ACETYLSALICYLIC ACID; ALPHA TOCOPHEROL; AMINOGUANIDINE; ANTIINFLAMMATORY AGENT; ENDOTHELIN A RECEPTOR ANTAGONIST; ENDOTHELIN B RECEPTOR ANTAGONIST; INFLIXIMAB; INSULIN; RUBOXISTAURIN;

ARTICLE; ATHEROSCLEROSIS; CARDIOVASCULAR DISEASE; CLINICAL TRIAL; DIABETES CONTROL; DIABETES MELLITUS; DRUG MECHANISM; HUMAN; HYPERGLYCEMIA; INSULIN RESISTANCE; INSULIN SENSITIVITY; INSULIN TREATMENT; NONHUMAN; PRIORITY JOURNAL; SIDE EFFECT;

EID: 0037231685     PISSN: 1520765X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S1520-765X(03)90041-1     Document Type: Article

References (109)

1. Biegelsen ES, Loscalzo J. Endothelial function and atherosclerosis. Coron Artery Dis 1999; 10: 241-56.
2. Du XL, Edelstein D, Dimmeler S, Ju Q, Sui C, Brownlee M. Hyperglycemia inhibits endothelial nitric oxide synthase activity by posttranslational modification at the Akt site. J Clin Invest 2001; 108: 1341-8.
3. Cosentino F, Hishikawa K, Katusic ZS, Luscher TF. High glucose increases nitric oxide synthase expression and superoxide anion generation in human aortic endothelial cells. Circulation 1997; 96: 25-8.
4. Hink U, Li H, Mollnau H, et al. Mechanisms underlying endothelial dysfunction in diabetes mellitus. Circ Res 2001; 88: E14-22.
5. Chen YL, Messina EJ. Dilation of isolated skeletal muscle arterioles by insulin is endothelium dependent and nitric oxide mediated. Am J Physiol 1996; 270: H2120-4.
6. Steinberg HO, Brechtel G, Johnson A, Fineberg N, Baron AD. Insulin-mediated skeletal muscle vasodilation is nitric oxide dependent. A novel action of insulin to increase nitric oxide release. J Clin Invest 1994; 94: 1172-9.
7. Scherrer U, Randin D, Vollenweider P, Vollenweider L, Nicod P. Nitric oxide release accounts for insulin's vascular effects in humans. J Clin Invest 1994; 94: 2511-5.
8. Duplain H, Burcelin R, Sartori C, et al. Insulin resistance, hyperlipidemia, and hypertension in mice lacking endothelial nitric oxide synthase. Circulation 2001; 104: 342-5.
9. Jiang ZY, Lin YW, Clemont A, et al. Characterization of selective resistance to insulin signaling in the vasculature of obese Zucker (fa/fa) rats. J Clin Invest 1999; 104: 447-57.
10. Kim F, Gallis B, Corson MA. TNF-alpha inhibits flow and insulin signaling leading to NO production in aortic endothelial cells. Am J Physiol Cell Physiol 2001; 280: C1057-65.
11. Montagnani M, Ravichandran LV, Chen H, Esposito DL, Quon MJ. Insulin receptor substrate-1 and phosphoinositide-dependent kinase-1 are required for insulin-stimulated production of nitric oxide in endothelial cells. Mol Endocrinol 2002; 16: 1931-42.
12. Zeng G, Nystrom FH, Ravichandran LV, et al. Roles for insulin receptor, PI3-kinase, and Akt in insulin-signaling pathways related to production of nitric oxide in human vascular endothelial cells. Circulation 2000; 101: 1539-45.
13. 2+ but requires phosphorylation by Akt at Ser(1179). J Biol Chem 2001; 276: 30392-8.
14. Zeng G, Quon MJ. Insulin-stimulated production of nitric oxide is inhibited by wortmannin. Direct measurement in vascular endothelial cells. J Clin Invest 1996; 98: 894-8.
15. Kuboki K, Jiang ZY, Takahara N, et al. Regulation of endothelial constitutive nitric oxide synthase gene expression in endothelial cells and in vivo: a specific vascular action of insulin. Circulation 2000; 101: 676-81.
16. Kinlay S, Behrendt D, Wainstein M, et al. Role of endothelin-1 in the active constriction of human atherosclerotic coronary arteries. Circulation 2001; 104: 1114-8.
17. Hopfner RL, Gopalakrishnan V. Endothelin: emerging role in diabetic vascular complications. Diabetologia 1999; 42: 1383-94.
18. Alberts GF, Peifley KA, Johns A, Kleha JF, Winkles JA. Constitutive endothelin-1 overexpression promotes smooth muscle cell proliferation via an external autocrine loop. J Biol Chem 1994; 269: 10112-8.
19. Park JY, Takahara N, Gabriele A, et al. Induction of endothelin-1 expression by glucose: an effect of protein kinase C activation. Diabetes 2000; 49: 1239-48.
20. Cardillo C, Nambi SS, Kilcoyne CM, et al. Insulin stimulates both endothelin and nitric oxide activity in the human forearm. Circulation 1999; 100: 820-5.
21. Verma S, Yao L, Stewart DJ, Dumont AS, Anderson TJ, McNeill JH, Endothelin antagonism uncovers insulin-mediated vasorelaxation in vitro and in vivo. Hypertension 2001; 37: 328-33.
22. Oliver FJ, de la Rubia G, Feener EP, et al. Stimulation ofendothelin-1 gene expression by insulin in endothelial cells. J Biol Chem 1991; 266: 23251-6.
23. Jiang ZY, Zhou QL, Chatterjee A, et al. Endothelin-1 modulates insulin signaling through phosphatidylinositol 3-kinase pathway in vascular smooth muscle cells. Diabetes 1999; 48: 1120-30.
24. Juan CC, Fang VS, Huang YJ, Kwok CF, Hsu YP, Ho LT. Endothelin-1 induces insulin resistance in conscious rats. Biochem Biophys Res Commun 1996; 227: 694-9.
25. Shah AM, MacCarthy PA. Paracrine and autocrine effects of nitric oxide on myocardial function. Pharmacol Ther 2000; 86: 49-86.
26. Recchia FA, Osorio JC, Chandler MP, et al. Reduced synthesis of NO causes marked alterations in myocardial substrate metabolism in conscious dogs. Am J Physiol Endocrinol Metab 2002; 282: E197-206.
27. Trochu JN, Bouhour JB, Kaley G, Hintze TH. Role of endothelium-derived nitric oxide in the regulation of cardiac oxygen metabolism: implications in health and disease. Circ Res 2000; 87: 1108-17.
28. Zhao G, Zhang X, Xu X, Wolin MS, Hintze TH. Depressed modulation of oxygen consumption by endogenous nitric oxide in cardiac muscle from diabetic dogs. Am J Physiol Heart Circ Physiol 2000; 279: H520-7.
29. Kelly RA, Eid H, Kramer BK, et al. Endothelin enhances the contractile responsiveness of adult rat ventricular myocytes to calcium by a pertussis toxin-sensitive pathway. J Clin Invest 1990; 86: 1164-71.
30. Lieu AT, Reid JJ. Changes in the responsiveness to endothelin-1 in isolated atria from diabetic rats. Eur J Pharmacol 1994; 261: 33-42.
31. Zachary I. Signaling mechanisms mediating vascular protective actions of vascular endothelial growth factor. Am J Physiol Cell Physiol 2001; 280: C1375-86.
32. Chou E, Suzuma I, Way KJ, et al. Decreased cardiac expression of vascular endothelial growth factor and its receptors in insulin-resistant and diabetic states: a possible explanation for impaired collateral formation in cardiac tissue. Circulation 2002; 105: 373-9.
33. Losordo DW, Vale PR, Hendel RC, et al. Phase 1/2 placebo-controlled, double-blind, dose-escalating trial of myocardial vascular endothelial growth factor 2 gene transfer by catheter delivery in patients with chronic myocardial ischemia. Circulation 2002; 105: 2012-8.
34. Way KJ, Opland DM, Isshiki K, et al. Impaired insulin-stimulated cardiac expression of vascular endothelial growth factor via the PI3K/Akt pathway may contribute to inadequate collateral formation in insulin resistant and diabetic states. Diabetes 2002; 51(suppl 2): A165.
35. Cusi K, Maezono K, Osman A, et al. Insulin resistance differentially affects the PI 3-kinase- and MAP kinase-mediated signaling in human muscle. J Clin Invest 2000; 105: 311-20.
36. Hermann C, Assmus B, Urbich C, Zeiher AM, Dimmeler S. Insulin-mediated stimulation of protein kinase Akt: A potent survival signaling cascade for endothelial cells. Arterioscler Thromb Vasc Biol 2000; 20: 402-9.
37. Gao F, Gao E, Yue TL, et al. Nitric oxide mediates the antiapoptotic effect of insulin in myocardial ischemia-reperfusion: the roles of PI3-kinase, Akt, and endothelial nitric oxide synthase phosphorylation. Circulation 2002; 105: 1497-502.
38. Marfella R, Esposito K, Giunta R, et al. Circulating adhesion molecules in humans: role of hyperglycemia and hyperinsulinemia. Circulation 2000; 101: 2247-51.
39. Aljada A, Saadeh R, Assian E, Ghanim H, Dandona P. Insulin inhibits the expression of intercellular adhesion molecule-1 by human aortic endothelial cells through stimulation of nitric oxide. J Clin Endocrinol Metab 2000; 85: 2572-5.
40. Albertini JP, Valensi P, Lormeau B, et al. Elevated concentrations of soluble E-selectin and vascular cell adhesion molecule-I in NIDDM. Effect of intensive insulin treatment. Diabetes Care 1998; 21: 1008-13.
41. Belke DD, Betuing S, Tuttle MJ, et al. Insulin signaling coordinately regulates cardiac size, metabolism, and contractile protein isoform expression. J Clin Invest 2002; 109: 629-39.
42. Young ME, McNulty P, Taegtmeyer H. Adaptation and maladaptation of the heart in diabetes: Part II: potential mechanisms. Circulation 2002; 105: 1861-70.
43. Russell RR III, Yin R, Caplan MJ, et al. Additive effects of hyperinsulinemia and ischemia on myocardial GLUT1 and GLUT4 translocation in vivo. Circulation 1998; 98: 2180-6.
44. Brownlee M, Vlassara H, Cerami A. Nonenzymatic glycosylation and the pathogenesis of diabetic complications. Ann Intern Med 1984; 101: 527-37.
45. Schmidt AM, Stern DM. RAGE: a new target for the prevention and treatment of the vascular and inflammatory complications of diabetes. Trends Endocrinol Metab 2000; 11: 368-75.
46. Nishikawa T, Edelstein D, Du XL, et al. Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Nature 2000; 404: 787-90.
47. Hunt JV, Dean RT, Wolff SP. Hydroxyl radical production and autoxidative glycosylation. Glucose autoxidation as the cause of protein damage in the experimental glycation model of diabetes mellitus and ageing. Biochem J 1988; 256: 205-12.
48. Suzuki S, Hinokio Y, Komatu K, et al. Oxidative damage to mitochondrial DNA and its relationship to diabetic complications. Diabetes Res Clin Pract 1999; 45: 161-8.
49. Tesfamariam B. Selective impairment of endothelium-dependent relaxations by prostaglandin endoperoxide. J Hypertens 1994; 12: 41-7.
50. Giugliano D, Ceriello A, Paolisso G. Oxidative stress and diabetic vascular complications. Diabetes Care 1996; 19: 257-67.
51. Lum H, Roebuck KA. Oxidant stress and endothelial cell dysfunction. Am J Physiol Cell Physiol 2001; 280: C719-41.
52. Mellor H, Parker PJ. The extended protein kinase C superfamily. Biochem J 1998; 332: 281-92.
53. Ishii H, Koya D, King GL. Protein kinase C activation and its role in the development of vascular complications in diabetes mellitus. J Mol Med 1998; 76: 21-31.
54. Inoguchi T, Battan R, Handler E, Sportsman JR, Heath W, King GL. Preferential elevation of protein kinase C isoform beta II and diacylglycerol levels in the aorta and heart of diabetic rats: differential reversibility to glycemic control by islet cell transplantation. Proc Natl Acad Sci USA 1992; 89: 11059-63.
55. Giles TD, Ouyang J, Kerut EK, et al. Changes in protein kinase C in early cardiomyopathy and in gracilis muscle in the BB/Wor diabetic rat. Am J Physiol 1998; 274: H295-307.
56. Nagpala PG, Malik AB, Vuong PT, Lum H. Protein kinase C beta I overexpression augments phorbol ester-induced increase in endothelial permeability. J Cell Physiol 1996; 166: 249-55.
57. Kuboki K, Jiang ZY, Takahara N, et al. Regulation of endothelial constitutive nitric oxide synthase gene expression in endothelial cells and in vivo: a specific vascular action of insulin. Circulation 2000; 101: 676-81.
58. Bohlen HG, Nase GP. Arteriolar nitric oxide concentration is decreased during hyperglycemia- induced betaII PKC activation. Am J Physiol Heart Circ Physiol 2001; 280: H621-7.
59. Nonaka A, Kiryu J, Tsujikawa A, et al. PKC-beta inhibitor (LY333531) attenuates leukocyte entrapment in retinal microcirculation of diabetic rats. Invest Ophthalmol Vis Sci 2000; 41: 2702-6.
60. Shiba T, Inoguchi T, Sportsman JR, Heath WF, Bursell S, King GL. Correlation of diacylglycerol level and protein kinase C activity in rat retina to retinal circulation. Am J Physiol 1993; 265: E783-93.
61. Wakasaki H, Koya D, Schoen FJ, et al. Targeted overexpression of protein kinase C beta2 isoform in myocardium causes cardiomyopathy. Proc Natl Acad Sci USA 1997; 94: 9320-5.
62. Takeishi Y, Chu G, Kirkpatrick DM, et al. In vivo phosphorylation of cardiac troponin I by protein kinase Cbeta2 decreases cardiomyocyte calcium responsiveness and contractility in transgenic mouse hearts. J Clin Invest 1998; 102: 72-8.
63. Ping P, Zhang J, Qiu Y, et al. Ischemic preconditioning induces selective translocation of protein kinase C isoforms epsilon and eta in the heart of conscious rabbits without subcellular redistribution of total protein kinase C activity. Circ Res 1997; 81: 404-14.
64. Chen L, Hahn H, Wu G, et al. Opposing cardioprotective actions and parallel hypertrophic effects of delta PKC and epsilon PKC. Proc Natl Acad Sci USA 2001; 98: 11114-9.
65. Williams B, Gallacher B, Patel H, Orme C. Glucose-induced protein kinase C activation regulates vascular permeability factor mRNA expression and peptide production by human vascular smooth muscle cells in vitro. Diabetes 1997; 46: 1497-503.
66. Koya D, Jirousek MR, Lin YW, et al. Characterization of protein kinase C beta isoform activation on the gene expression of transforming growth factor-beta, extracellular matrix components, and prostanoids in the glomeruli of diabetic rats. J Clin Invest 1997; 100: 115-26.
67. Way KJ, Isshiki K, Suzuma K, et al. Expression of connective tissue growth factor is increased in injured myocardium associated with protein kinase C beta2 activation and diabetes. Diabetes 2002; 51: 2709-18.
68. Wang DL, Wung BS, Peng YC, Wang JJ, Mechanical strain increases endothelin-1 gene expression via protein kinase C pathway in human endothelial cells. J Cell Physiol 1995; 163: 400-6.
69. Aiello LP, Bursell SE, Clermont A, et al. Vascular endothelial growth factor-induced retinal permeability is mediated by protein kinase C in vivo and suppressed by an orally effective beta-isoform-selective inhibitor. Diabetes 1997; 46: 1473-80.
70. Schiffrin EL, Touyz RM. Vascular biology of endothelin. J Cardiovasc Pharmacol 1998; 32(suppl 3): S2-13.
71. Tomlinson DR. Mitogen-activated protein kinases as glucose transducers for diabetic complications. Diabetologia 1999; 42: 1271-81.
72. Suzuma K, Takahara N, Suzuma I, et al. Characterization of protein kinase C beta isoform's action on retinoblastoma protein phosphorylation, vascular endothelial growth factor-induced endothelial cell proliferation, and retinal neovascularization. Proc Natl Acad Sci USA 2002; 99: 721-6.
73. Hamada Y, Araki N, Koh N, Nakamura J, Horiuchi S, Hotta N. Rapid formation of advanced glycation end products by intermediate metabolites of glycolytic pathway and polyol pathway. Biochem Biophys Res Commun 1996; 228: 539-43.
74. Wells-Knecht MC, Thorpe SR, Baynes JW. Pathways of formation of glycoxidation products during glycation of collagen. Biochemistry 1995; 34: 15134-41.
75. Yan SD, Schmidt AM, Anderson GM, et al. Enhanced cellular oxidant stress by the interaction of advanced glycation end products with their receptors/binding proteins. J Biol Chem 1994; 269: 9889-97.
76. Anderson MM, Requena JR, Crowley JR, Thorpe SR, Heinecke JW. The myeloperoxidase system of human phagocytes generates Nepsilon- (carboxymethyl)lysine on proteins: a mechanism for producing advanced glycation end products at sites of inflammation. J Clin Invest 1999; 104: 103-13.
77. Inoguchi T, Li P, Umeda F, et al. High glucose level and free fatty acid stimulate reactive oxygen species production through protein kinase C-dependent activation of NAD(P)H oxidase in cultured vascular cells. Diabetes 2000; 49: 1939-45.
78. Kim YS, Kim BC, Song CY, Hong HK, Moon KC, Lee HS. Advanced glycosylation end products stimulate collagen mRNA synthesis in mesangial cells mediated by protein kinase C and transforming growth factor-beta. J Lab Clin Med 2001; 138: 59-68.
79. Lander HM, Tauras JM, Ogiste JS, Hori O, Moss RA, Schmidt AM. Activation of the receptor for advanced glycation end products triggers a p21(ras)-dependent mitogen-activated protein kinase pathway regulated by oxidant stress. J Biol Chem 1997; 272: 17810-4.
80. Brownlee M, Vlassara H, Kooney A, Ulrich P, Cerami A. Aminoguanidine prevents diabetes-induced arterial wall protein cross-linking. Science 1986; 232: 1629-32.
81. Friedman EA. Advanced glycosylated end products and hyperglycemia in the pathogenesis of diabetic complications. Diabetes Care 1999; 22(suppl 2): B65-71.
82. Wautier JL, Zoukourian C, Chappey O, et al. Receptor-mediated endothelial cell dysfunction in diabetic vasculopathy. Soluble receptor for advanced glycation end products blocks hyperpermeability in diabetic rats. J Clin Invest 1996; 97: 238-43.
83. Cameron NE, Cotter MA. Neurovascular dysfunction in diabetic rats. Potential contribution of autoxidation and free radicals examined using transition metal chelating agents. J Clin Invest 1995; 96: 1159-63.
84. Cameron NE, Cotter MA, Archibald V, Dines KC, Maxfield EK. Anti-oxidant and pro-oxidant effects on nerve conduction velocity, endoneurial blood flow and oxygen tension in non-diabetic and streptozotocin-diabetic rats. Diabetologia 1994; 37: 449-59.
85. Nagamatsu M, Nickander KK, Schmelzer JD, et al. Lipoic acid improves nerve blood flow, reduces oxidative stress, and improves distal nerve conduction in experimental diabetic neuropathy. Diabetes Care 1995; 18: 1160-7.
86. Lal MA, Korner A, Matsuo Y, et al. Combined antioxidant and COMT inhibitor treatment reverses renal abnormalities in diabetic rats. Diabetes 2000; 49: 1381-9.
87. Kowluru RA, Tang J, Kern TS. Abnormalities of retinal metabolism in diabetes and experimental galactosemia. VII. Effect of long-term administration of antioxidants on the development of retinopathy. Diabetes 2001; 50: 1938-42.
88. Bursell SE, Clermont AC, Aiello LP, et al. High-dose vitamin E supplementation normalizes retinal blood flow and creatinine clearance in patients with type I diabetes. Diabetes Care 1999; 22: 1245-51.
89. Stephens NG, Parsons A, Schofield PM, Kelly F, Cheeseman K, Mitchinson MJ. Randomised controlled trial of vitamin E in patients with coronary disease: Cambridge Heart Antioxidant Study (CHAOS). Lancet 1996; 347: 781-6.
90. Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico. Lancet 1999; 354: 447-55.
91. Yusuf S, Dagenais G, Pogue J, Bosch J, Sleight P. Vitamin E supplementation and cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 2000; 342: 154-60.
92. Lee IK, Koya D, Ishi H, Kanoh H, King GL. d-Alpha-tocopherol prevents the hyperglycemia induced activation of diacylglycerol (DAG)-protein kinase C (PKC) pathway in vascular smooth muscle cell by an increase of DAG kinase activity. Diabetes Res Clin Pract 1999; 45: 183-90.
93. Studer RK, Craven PA, DeRubertis FR. Antioxidant inhibition of protein kinase C-signaled increases in transforming growth factor-beta in mesangial cells. Metabolism 1997; 46: 918-25.
94. Verma S, Arikawa E, McNeill JH. Long-term endothelin receptor blockade improves cardiovascular function in diabetes. Am J Hypertens 2001; 14: 679-87.
95. Kanie N, Kamata K. Effects of chronic administration of the novel endothelin antagonist J-104132 on endothelial dysfunction in streptozotocin-induced diabetic rat. Br J Pharmacol 2002; 135: 1935-42.
96. Way KJ, Chou E, King GL. Identification of PKC-isoform-specific biological actions using pharmacological approaches. Trends Pharmacol Sci 2000; 21: 181-7.
97. Schechtman D, Mochly-Rosen D. Adaptor proteins in protein kinase C-mediated signal transduction. Oncogene 2001; 20: 6339-47.
98. Danis RP, Bingaman DP, Jirousek M, Yang Y. Inhibition of intraocular neovascularization caused by retinal ischemia in pigs by PKCbeta inhibition with LY333531. Invest Ophthalmol Vis Sci 1998; 39: 171-9.
99. Nakamura J, Kato K, Hamada Y, et al. A protein kinase C-beta-selective inhibitor ameliorates neural dysfunction in streptozotocin-induced diabetic rats. Diabetes 1999; 48: 2090-5.
100. Ido Y, Chang KC, Lejeune WS, et al. Vascular dysfunction induced by AGE is mediated by VEGF via mechanisms involving reactive oxygen species, guanylate cyclase, and protein kinase C. Microcirculation 2001; 8: 251-63.
101. Ren S, Shatadal S, Shen GX. Protein kinase C-beta mediates lipoprotein-induced generation of PAI-1 from vascular endothelial cells. Am J Physiol Endocrinol Metab 2000; 278: E656-62.
102. Dekker LV, Leitges M, Altschuler G, et al. Protein kinase C-beta contributes to NADPH oxidase activation in neutrophils. Biochem J 2000; 347: 285-9.
103. Chen S, Apostolova MD, Cherian MG, Chakrabarti S. Interaction of endothelin-1 with vasoactive factors in mediating glucose-induced increased permeability in endothelial cells. Lab Invest 2000; 80: 1311-21.
104. Xia P, Aiello LP, Ishii H, et al. Characterization of vascular endothelial growth factor's effect on the activation of protein kinase C, its isoforms, and endothelial cell growth. J Clin Invest 1996; 98: 2018-26.
105. Ross R. Atherosclerosis: an inflammatory disease. N Engl J Med 1999; 340: 115-26.
106. Collins T, Cybulsky MI. NF-kappaB: pivotal mediator or innocent bystander in atherogenesis? J Clin Invest 2001; 107: 255-64.
107. Yuan M, Konstantopoulos N, Lee J, et al. Reversal of obesity-and diet-induced insulin resistance with salicylates or targeted disruption of Ikkbeta. Science 2001; 293: 1673-7.
108. Gao Z, Hwang D, Bataille F, et al. Serine phosphorylation of insulin receptor substrate 1 (IRS-1) by inhibitor kappaB kinase (IKK) complex. J Biol Chem 2002; 25.
109. Hurlimann D, Forster A, Noll G, et al. Anti-tumor necrosis factor-alpha treatment improves endothelial function in patients with rheumatoid arthritis. Circulation 2002; 106: 2184-7.