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Horm Metab Res 2006; 38(11): 691-705
DOI: 10.1055/s-2006-955081
Review

© Georg Thieme Verlag KG Stuttgart · New York

Macroangiopathy in Adults and Children with Diabetes: From Molecular Mechanisms to Vascular Damage (Part 1)

D. Di Marzio 1 , A. Mohn 1 , Z. H. Mokini 1 , C. Giannini 1 , F. Chiarelli 1 , 2
  • 1Department of Pediatrics, University of Chieti, Italy
  • 2Department of Pediatrics, University of Florence “Anna Meyer” Children's Hospital, Florence, Italy
Further Information

Publication History

Received 30 November 2005

Accepted after second revision 14 August 2006

Publication Date:
16 November 2006 (online)

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Abstract

Type 2 diabetes mellitus (T2DM) is an increasing problem in childhood; however type 1 diabetes mellitus (T1DM) remains by far the most common type of diabetes in this age group. In this review we will focus on T1DM, because this will have the greatest implication for patients diagnosed in childhood. During the atherosclerotic process, several molecular, receptorial and cellular factors provide a continous mechanism of vascular damage. In diabetic children this state seems to be enhanced and facilitated so that accelerated atherosclerosis is associated with an increased risk of cardiovascular events in respect to the non diabetic population. Hyperglycemia per se and associated with diabetes is an important risk factor for atherosclerosis. At present a substantial part of children with diabetes do not reach satisfactory glycemic control. Other risk factors for the development and progression of atherosclerosis may be inherited or develop in the course of the disease: hypertension, dyslipidemia, insulin resistance, obesity, cigarette smoking, physical inactivity, disturbance of platelet function, coagulation and fibrinolysis. The development and progression of atherosclerosis should be blocked at an early age, if possible. Primary prevention to all risk factors for cardiovascular disease is important and intervention is indicated if necessary. At the moment the best therapeutic strategy is to maintain metabolic control at a physiologic level and perform screening and early intervention for vascular complications.

Key words

Diabetes mellitus - hyperglycemia - atherosclerosis - TNF-α - macrophages - smooth muscle cells - lipids - macroangiopathy - nitric oxide

References

  • 1 Expert Committee on the Diagnosis and Classification of Diabetes Mellitus . Report of the expert committee on the diagnosis and classification of diabetes mellitus.  Diabetes Care. 2003;  26 5-20
    PubMedGoogle Scholar
  • 2 King H, Aubert RE, Herman WH. Global burden of diabetes, 1995-2025: prevalence, numerical estimates, and projections.  Diabetes Care. 1998;  21 1414-1431
    CrossrefPubMedGoogle Scholar
  • 3 Dubois L, Girard M. Early determinants of overweight at 4.5 years in a population-based longitudinal study.  Int J Obes (Lond). 30 610-617
    PubMedGoogle Scholar
  • 4 Brownlee M. Biochemistry and molecular cell biology of diabetic complications.  Nature. 2001;  414 813-820
    CrossrefPubMedGoogle Scholar
  • 5 Fuster V, Moreno PR, Fayad ZA, Corti R, Badiman JJ. Atherothrombosis and high-risk claque.  JACC. 2005;  46 937-954
    PubMedGoogle Scholar
  • 6 Entmacher PS, Root HF, Marks HH. Longevity of diabetic patients in recent years.  Diabetes. 1964;  13 373-377
    PubMedGoogle Scholar
  • 7 Orchard TJ, Stevens LK, Forrest KY-Z, Fuller JH. Cardiovascular disease in insulin dependent diabetes mellitus: similar rates but different risk factors in the US compared with Europe.  Int J Epidemiol. 1998;  27 976-983
    CrossrefPubMedGoogle Scholar
  • 8 Krolewski AS, Kosinski EJ, Warram JH, Leland OS, Busick EJ, Asmal AC, Rand LI, Christlieb AR, Bradley RF, Kahn CR. Magnitude and determinants of coronary artery disease in juvenile-onset, insulin-dependent diabetes mellitus.  Am J Cardiol. 1987;  59 750-755
    CrossrefPubMedGoogle Scholar
  • 9 Laing SP, Swerdlow AJ, Slater SD, Botha JL, Burden AC, Waugh NR, Smith AW, Hill RD, Bingley PJ, Patterson CC, Qiao Z, Keen H. The British Diabetic Association Cohort Study, I: all-cause mortality in patients with insulin-treated diabetes mellitus.  Diab Med. 1999;  16 459-465
    CrossrefPubMedGoogle Scholar
  • 10 Laing SP, Swerdlow AJ, Slater SD, Burden AC, Morris A, Waugh NR, Gathing W, Bingley PJ, Patterson CC. Mortality from heart disease in a cohort of 23,000 patients with insulin-treated diabetes.  Diabetologia. 2003;  46 760-765
    CrossrefPubMedGoogle Scholar
  • 11 Sijbrands EJG, Westendorp RGJ, Defesche JC, deMeier PHEM, Smelt AHM, Kastelein JPJ. Mortality over two centuries in large pedigree with familial hypercholesterolaemia: family tree mortality study.  BMJ. 2001;  322 1019-1022
    CrossrefPubMedGoogle Scholar
  • 12 Tuomiletho J, Borch-Johnsen K, Molarius A, Forsén T, Rastenyte D, Sarti C, Reunanen A. Incidence of cardiovascular disease in type 1 (insulin-dependent) diabetic subjects with and without diabetic nephropathy in Finland.  Diabetologia. 1998;  41 784-790
    CrossrefPubMedGoogle Scholar
  • 13 Koivisto VA, Stevens LK, Mattock M, Ebeling P, Muggeo M, Stephenson J, Idzior-Walus B. The EURODIAB IDDM Complications. Study Group. Cardiovascular disease and its risk factors in IDDM in Europe.  Diabetes Care. 1996;  19 689-697
    CrossrefPubMedGoogle Scholar
  • 14 Holman RL. Atherosclerosis: a pediatric nutrition problem.  Am J Clin Nutr. 1961;  9 565-569
    PubMedGoogle Scholar
  • 15 Koivisto VA, Stevens LK, Mattock M, Ebeling P, Muggeo M, Stephenson J, Idzior-Walus B. The EURODIAB IDDM Complications. Study Group. Cardiovascular disease and its risk factors in IDDM in Europe.  Diabetes Care. 1996;  19 689-697
    CrossrefPubMedGoogle Scholar
  • 16 Orchard TJ, Stevens LK, Forrest KY-Z, Fuller JH. Cardiovascular disease in insulin dependent diabetes mellitus: similar rates but different risk factors in the US compared with Europe.  Int J Epidemiol. 1998;  27 976-983
    CrossrefPubMedGoogle Scholar
  • 17 Strong JP, McGill HC. The natural history of coronary atherosclerosis.  Am J Pathol. 1962;  40 37-49
    PubMedGoogle Scholar
  • 18 Strong JP, Malcom GT, McMahan CA, Tracy RE, Newman WP, Herderick EE, Cornhill JF. Prevalence and extent of atherosclerosis in adolescents and young adults: implications for prevention from the Pathobiological Determinants of Atherosclerosis in Youth Study.  JAMA. 1999;  281 727-735
    CrossrefPubMedGoogle Scholar
  • 19 McGill Jr HC, McMahan CA, Malcom GT. Effects of serum lipoproteins and smoking on atherosclerosis in young men and women.  Arterioscler Thromb Vasc Biol. 1997;  17 95-106
    PubMedGoogle Scholar
  • 20 McGill Jr HC, McMahan CA, Tracy RE, Oalmann MC, Cornhill JF, Herderick EE, Strong JP. Relation of a postmortem renal index of hypertension to atherosclerosis and coronary artery size in young men and women.  Arterioscler Thromb Vasc Biol. 1998;  18 1108-1118
    PubMedGoogle Scholar
  • 21 McGill Jr HC, McMahan CA, Malcom GT, Oalmann MC, Strong JP. Relation of glycohemoglobin and adiposity to atherosclerosis in youth. Pathobiological Determinants of Atherosclerosis in Youth (PDAY) Research Group.  Arterioscler Thromb Vasc Biol. 1995;  15 431-440
    PubMedGoogle Scholar
  • 22 McGill Jr HC, Strong JP, Tracy RE, McMahan CA, Oalmann MC. Relation of a postmortem renal index of hypertension to atherosclerosis in youth. The Pathobiological Determinants of Atherosclerosis in Youth (PDAY) Research Group.  Arterioscler Thromb Vasc Biol. 1995;  15 2222-2228
    PubMedGoogle Scholar
  • 23 Tuzcu EM, Kapadia SR, Tutar E, Ziada KM, Hobbs RE, McCarthy PM, Young JB, Nissen SE. High Prevalence of Coronary Atherosclerosis in Asymptomatic Teenagers and Young Adults. Evidence from Intravascular Ultrasound.  Circulation. 2001;  103 2705-2710
    PubMedGoogle Scholar
  • 24 Nishimura RA, Edwards WD, Warnes CA, Reeder GS, Holmes Jr DR, Tajik AJ, Yock PG. Intravascular ultrasound imaging: in vitro validation and pathologic correlation.  J Am Coll Cardiol. 1990;  16 145-154
    PubMedGoogle Scholar
  • 25 Kennedy JW, Kaiser GC, Fisher LD, Fritz JK, Myers W, Mudd JG, Ryan TJ. Clinical and angiographic predictors of operative mortality from the collaborative study in coronary artery surgery (CASS).  Circulation. 1981;  63 793-802
    PubMedGoogle Scholar
  • 26 Li S, Chen W, Srinivasan SR, Bond MG, Tang R, Urbina EM, Berenson GS. Childhood cardiovascular risk factors and carotid vascular changes in adulthood. The Bogalusa Heart Study.  JAMA. 2003;  290 2271-2276
    CrossrefPubMedGoogle Scholar
  • 27 Raitakari OT, Juonala M, Kähönen M, Taittonen L, Laitinen T, Mäki-Torkko N, Jävisalo MJ, Uhari M, Jokinen E, Rönnamaa T, Åkerblom HK, Viikari JSA. Cardiovascular risk factors in childhood and carotid artery intima-media thickness in adulthood. The Cardiovascular Risk in Young Finns Study.  JAMA. 2003;  290 2277-2283
    CrossrefPubMedGoogle Scholar
  • 28 Faxon DP, Creager MA, Smith Jr SC, Pasternak RC, Olin JW, Bettmann MA, Criqui MH, Milani RV, Loscalzo J, Kaufman JA, Jones DW, William H. Atherosclerotic Vascular Disease Conference: Executive Summary: Atherosclerotic Vascular Disease Conference Proceeding for Healthcare Professionals From a Special Writing Group of the American Heart Association.  Circulation. 2004;  109 2595-2604
    CrossrefPubMedGoogle Scholar
  • 29 Naghavi M, Libby P, Falk E, Casscells SW, Litovsky S, Rumberger J, Badimon JJ, Stefanadis C, Moreno P, Pasterkamp G, Fayad Z, Stone PH, Waxman S, Raggi P, Madjid M, Zarrabi A, Burke A, Yuan C, Fitzgerald PJ, Siscovick DS, de Korte CL, Aikawa M, Airaksinen KEJ, Assmann G, Becker CR, Chesebro JH, Farb A, Galis ZS, Jackson C, Jang I-K, Koenig W, Lodder RA, March K, Demirovic J, Navab M, Priori SG, Rekhter MD, Bahr R, Grundy SM, Mehran R, Colombo A, Boerwinkle E, Ballantyne C, Insull Jr W, Schwartz RS, Vogel R, Serruys PW, Hansson GK, Faxon DP, Kaul S, Drexler H, Greenland P, Muller JE, Virmani R, Ridker PM, Zipes DP, Shah PK, Willerson JT. From Vulnerable Plaque to Vulnerable Patient: A Call for New Definitions and Risk Assessment Strategies: Part I.  Circulation. 2003;  108 1664-1672
    CrossrefPubMedGoogle Scholar
  • 30 Geng YJ, Libby P. Progression of atheroma: a struggle between death and procreation.  Arterioscler Thromb Vasc Biol. 2002;  22 1370-1380
    CrossrefPubMedGoogle Scholar
  • 31 van der Wal AC, Becker AE, van der Loos CM, Das PK. Site of intimal rupture or erosion of thrombosed coronary atherosclerotic plaques is characterized by an inflammatory process irrespective of the dominant plaque morphology.  Circulation. 1994;  89 36-44
    PubMedGoogle Scholar
  • 32 Stary HC, Chandler AB, Dinsmore RE. A definition of advanced types of atherosclerotic lesions and a histological classification of atherosclerosis. A report from the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association.  Circulation. 1995;  92 1355-1374
    CrossrefPubMedGoogle Scholar
  • 33 Stary HC, Chandler AB, Glagov S, Guyton JR, Insull Jr W, Rosenfeld ME, Schaffer SA, Schwartz CJ, Wagner WD, Wissler RW. A definition of initial, fatty streak, and intermediate lesions of atherosclerosis. A report from the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association.  Circulation. 1994;  89 2462-2478
    PubMedGoogle Scholar
  • 34 Stary HC. Lipid and macrophage accumulations in arteries of children and the development of atherosclerosis.  Am J Clin Nutr. 2000;  72 ((Suppl 5)) 1297S-1306S
    PubMedGoogle Scholar
  • 35 Berenson GS, Wattigney WA, Tracy RE, Newman WP, Srinivasan SR, Webber LS, Dalferes Jr ER, Strong JP. Atherosclerosis of the aorta and coronary arteries and cardiovascular risk factors in persons aged 6 to 30 years and studied at necropsy (The Bogalusa Heart Study).  Am J Cardiol. 1992;  70 851-858
    CrossrefPubMedGoogle Scholar
  • 36 McGill Jr HC, McMahan CA, Herderick EE, Malcom GT, Tracy RE, Strong JP. Origin of atherosclerosis in childhood and adolescence.  Am J Clin Nutr. 2000;  72 ((Suppl 5)) 1307S-1315S
    PubMedGoogle Scholar
  • 37 Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s.  Nature. 1993;  362 ((6423)) 801-809
    CrossrefPubMedGoogle Scholar
  • 38 Hoymans VY, Bosmans JM, Ieven M, Vrints CJ. Chlamydia pneumoniae and atherosclerosis.  Acta Chir Belg. 2002;  102 317-322
    PubMedGoogle Scholar
  • 39 Liuba P, Pesonen E. Infection and early atherosclerosis: does the evidence support causation?.  Acta Paediatr. 2005;  94 643-651
    CrossrefPubMedGoogle Scholar
  • 40 Santilli F, Cipollone F, Mezzetti A, Chiarelli F. The role of nitric oxide in the development of diabetic angiopathy.  Horm Metab Res. 2004;  36 319-335
    Article in Thieme ConnectPubMedGoogle Scholar
  • 41 Garcia-Cardena G, Comander J, Anderson KR, Blackman BR, Gimbrone Jr MA. Biomechanical activation of vascular endothelium as a determinant of its functional phenotype.  Proc Natl Acad Sci USA. 2001;  98 4478-4485
    CrossrefPubMedGoogle Scholar
  • 42 Wasserman SM, Mehraban F, Komuves LG, Yang RB, Tomlinson JE, Zhang Y, Spriggs F, Topper JN. Gene expression profile of human endothelial cells exposed to sustained fluid shear stress.  Physiol Genomics. 2002;  12 13-23
    PubMedGoogle Scholar
  • 43 Wernig F, Xu Q. Mechanical stress-induced apoptosis in the cardiovascular system.  Prog Biophys Mol Biol. 2002;  78 105-137
    PubMedGoogle Scholar
  • 44 Cunningham KS, Gotlieb AI. The role of shear stress in the pathogenesis of atherosclerosis.  Lab Invest. 2005;  85 9-23
    CrossrefPubMedGoogle Scholar
  • 45 Dai G, Kaazempur-Mofrad MR, Natarajan S, Zhang Y, Vaughn S, Blackman BR, Kamm RD, Garcia-Cardena G, Gimbrone Jr MA. Distinct endothelial phenotypes evoked by arterial waveforms derived from atherosclerosis-susceptible and -resistant regions of human vasculature.  Proc Natl Acad Sci USA. 2004;  101 14871-14876
    CrossrefPubMedGoogle Scholar
  • 46 Li S, Huang NF, Hsu S. Mechanotransduction in endothelial cell migration.  J Cell Biochem. 2005;  96 1110-1126
    CrossrefPubMedGoogle Scholar
  • 47 Soccio RE, Breslow JL. Intracellular cholesterol transport.  Arterioscler Thromb Vasc Biol. 2004;  24 1150-1160
    PubMedGoogle Scholar
  • 48 Steinberg D. Atherogenesis in perspective: hypercholesterolemia and inflammation as partners in crime.  Nat Med. 2002;  8 1211-1217
    CrossrefPubMedGoogle Scholar
  • 49 Steinberg D. Low density lipoprotein oxidation and its pathobiological significance.  J Biol Chem. 1997;  272 20963-20966
    CrossrefPubMedGoogle Scholar
  • 50 Knowles JW, Reddick RL, Jennette JC, Shesely EG, Smithies O, Maeda N. Enhanced atherosclerosis and kidney dysfunction in eNOS(-/-)Apoe(-/-) mice are ameliorated by enalapril treatment.  J Clin Invest. 2000;  105 451-458
    PubMedGoogle Scholar
  • 51 Steinberg D, Witztum JL. Is the oxidative modification hypothesis relevant to human atherosclerosis? Do the antioxidant trials conducted to date refute the hypothesis?.  Circulation. 2002;  105 2107-2111
    CrossrefPubMedGoogle Scholar
  • 52 Fazio S, Linton MF. The inflamed plaque: cytokine production and cellular cholesterol balance in the vessel wall.  Am J Cardiol. 2001;  88 12E-15E
    CrossrefPubMedGoogle Scholar
  • 53 Collins T, Cybulsky MI. NF-kB: pivotal mediator or innocent bystander in atherogenesis?.  J Clin Invest. 2001;  107 255-264
    CrossrefPubMedGoogle Scholar
  • 54 Skalen K, Gustafsson M, Rydberg EK, Hulten LM, Wiklund O, Innerarity TL, Boren J. Subendothelial retention of atherogenic lipoproteins in early atherosclerosis.  Nature. 2002;  417 750-754
    PubMedGoogle Scholar
  • 55 Schaefer EJ, Lamon-Fava S, Jenner JL, McNamara JR, Ordovas JM, Davis CE, Abolafia JM, Lippel K, Levy RI. Lipoprotein(a) levels and risk of coronary heart disease in men.  JAMA. 1994;  271 999-1003
    CrossrefPubMedGoogle Scholar
  • 56 Hajjar KA, Nachman RL. The role of lipoprotein(a) in atherogenesis and thrombosis.  Annu Rev Med. 1996;  47 423-442
    CrossrefPubMedGoogle Scholar
  • 57 Poon M, Zhang X, Dunsky KG, Taubman MB, Harpel PC. Apolipoprotein(a) induces monocyte chemotactic activity in human vascular endothelial cells.  Circulation. 1997;  96 2514-2519
    PubMedGoogle Scholar
  • 58 Libby P, Ridker PM, Maseri A. Inflammation and atherosclerosis.  Circulation. 2002;  105 1135-1143
    CrossrefPubMedGoogle Scholar
  • 59 Libby P. Inflammation in atherosclerosis.  Nature. 2002;  420 868-874
    CrossrefPubMedGoogle Scholar
  • 60 Kher N, Marsh JD. Pathobiology of atherosclerosis-a brief review.  Semin Thromb Hemost. 2004;  30 665-672
    Article in Thieme ConnectPubMedGoogle Scholar
  • 61 Lusis AJ. Atherosclerosis.  Nature. 2000;  407 233-241
    CrossrefPubMedGoogle Scholar
  • 62 Burke-Gaffney A, Brooks AV, Bogle RG. Regulation of chemokine expression in atherosclerosis.  Vascul Pharmacol. 2002;  38 283-292
    CrossrefPubMedGoogle Scholar
  • 63 Cybulsky MI, Fries JW, Williams AJ, Sultan P, Eddy R, Byers M, Shows T, Gimbrone Jr MA, Collins T. Gene structure, chromosomal location, and basis for alternative mRNA splicing of the human VCAM1 gene.  Proc Natl Acad Sci USA. 1991;  88 7859-7863
    CrossrefPubMedGoogle Scholar
  • 64 Li H, Cybulsky MI, Gimbrone Jr MA, Libby P. An atherogenic diet rapidly induces VCAM-1, a cytokine-regulatable mononuclear leukocyte adhesion molecule, in rabbit aortic endothelium.  Arterioscler Thromb. 1993;  13 197-204
    PubMedGoogle Scholar
  • 65 Cybulsky MI, Iiyama K, Li H, Zhu S, Chen M, Iiyama M, Davis V, Gutierrez-Ramos JC, Connelly PW, Milstone DS. A major role for VCAM-1, but not ICAM-1, in early atherosclerosis.  J Clin Invest. 2001;  107 1255-1262
    CrossrefPubMedGoogle Scholar
  • 66 Hillis GS. Soluble integrin adhesion receptors and atherosclerosis: much heat and a little light?.  J Hum Hypertens. 2003;  17 449-453
    CrossrefPubMedGoogle Scholar
  • 67 Takahashi K, Takeya M, Sakashita N. Multifunctional roles of macrophages in the development and progression of atherosclerosis in humans and experimental animals.  Med Electron Microsc. 2002;  35 179-203
    CrossrefPubMedGoogle Scholar
  • 68 Gu L, Okada Y, Clinton SK, Gerard C, Sukhova GK, Libby P, Rollins BJ. Absence of monocyte chemoattractant protein-1 reduces atherosclerosis in low density lipoprotein receptor-deficient mice.  Mol Cell. 1998;  2 275-281
    CrossrefPubMedGoogle Scholar
  • 69 Boring L, Gosling J, Cleary M, Charo IF. Decreased lesion formation in CCR2-/- mice reveals a role for chemokines in the initiation of atherosclerosis.  Nature. 1998;  394 894-897
    CrossrefPubMedGoogle Scholar
  • 70 Gosling J, Slaymaker S, Gu L, Tseng S, Zlot CH, Young SG, Rollins BJ, Charo IF. MCP-1 deficiency reduces susceptibility to atherosclerosis in mice that overexpress human apolipoprotein B.  J Clin Invest. 1999;  103 773-778
    CrossrefPubMedGoogle Scholar
  • 71 Boyle JJ. Macrophage activation in atherosclerosis: pathogenesis and pharmacology of plaque rupture.  Curr Vasc Pharmacol. 2005;  3 63-68
    CrossrefPubMedGoogle Scholar
  • 72 Febbraio M, Podrez EA, Smith JD, Hajjar DP, Hazen SL, Hoff HF, Sharma K, Silverstein RL. Targeted disruption of the class B scavenger receptor CD36 protects against atherosclerotic lesion development in mice.  J Clin Invest. 2000;  105 1049-1056
    PubMedGoogle Scholar
  • 73 Yoshida H, Kondratenko N, Green S, Steinberg D, Quehenberger O. Identification of the lectin-like receptor for oxidized low-density lipoprotein in human macrophages and its potential role as a scavenger receptor.  Biochem J. 1998;  34 9-13
    PubMedGoogle Scholar
  • 74 Mehta JL, Li DY. Identification and autoregulation of receptor for OX-LDL in cultured human coronary artery endothelial cells.  Biochem Biophys Res Commun. 1998;  248 511-514
    CrossrefPubMedGoogle Scholar
  • 75 Nagase M, Abe J, Takahashi K, Ando J, Hirose S, Fujita T. Genomic organization and regulation of expression of the lectin-like oxidized low-density lipoprotein receptor (LOX-1) gene.  J Biol Chem. 1998;  273 33702-33707
    CrossrefPubMedGoogle Scholar
  • 76 Peter Libby. Vascular Biology of Atherosclerosis: Overview and State of the Art.  Am J Cardiol. 2003;  91 ((Suppl)) 3A-6A
    PubMedGoogle Scholar
  • 77 Schonbeck U, Libby P. CD40 signaling and plaque instability.  Circ Res. 2001;  89 1092-1103
    CrossrefPubMedGoogle Scholar
  • 78 Schonbeck U, Libby P. The CD40/CD154 reactor/ligand dyad.  Cell Mol Life Sci. 2001;  58 4-43
    PubMedGoogle Scholar
  • 79 Krettek A, Sukhova GK, Schonbeck U, Libby P. Enhanced expression of CD44 variants in human atheroma and abdominal aortic aneurysm: possible role for a feedback loop in endothelial cells.  Am J Pathol. 2004;  165 1571-1581
    PubMedGoogle Scholar
  • 80 Boisvert WA, Curtiss LK, Terkeltaub RA. Interleukin-8 and its receptor CXCR2 in atherosclerosis.  Immunol Res. 2000;  21 129-137
    PubMedGoogle Scholar
  • 81 Boisvert WA. Modulation of atherogenesis by chemokines.  Trends Cardiovasc Med. 2004;  14 161-165
    CrossrefPubMedGoogle Scholar
  • 82 Umehara H, Bloom ET, Okazaki T, Nagano Y, Yoshie O, Imai T. Fractalkine in vascular biology: from basic research to clinical disease.  Arterioscler Thromb Vasc Biol. 2004;  24 34-40
    CrossrefPubMedGoogle Scholar
  • 83 Tangirala RK, Bischoff ED, Joseph SB, Wagner BL, Walczak R, Laffitte BA, Daige CL, Thomas D, Heyman RA, Mangelsdorf DJ, Wang X, Lusis AJ, Tontonoz P, Schulman IG. Identification of macrophage liver X receptors as inhibitors of atherosclerosis.  Proc Natl Acad Sci USA. 2002;  99 11896-11901
    CrossrefPubMedGoogle Scholar
  • 84 Young JL, Libby P, Schonbeck U. Cytokines in the pathogenesis of atherosclerosis.  Thromb Haemost. 2002;  88 554-567
    PubMedGoogle Scholar
  • 85 Lim YC, Garcia-Cardena G, Allport JR, Zervoglos M, Connolly AJ, Gimbrone Jr MA, Luscinskas FW. Heterogeneity of endothelial cells from different organ sites in T-cell subset recruitment.  Am J Pathol. 2003;  162 1591-1601
    PubMedGoogle Scholar
  • 86 Tall AR, Jiang X, Luo Y, Silver D. 1999 George Lyman Duff memorial lecture: lipid transfer proteins, HDL metabolism, and atherogenesis.  Arterioscler Thromb Vasc Biol. 2000;  20 1185-1188
    PubMedGoogle Scholar
  • 87 Lawn RM, Wade DP, Garvin MR, Wang X, Schwartz K, Porter JG, Seilhamer JJ, Vaughan AM, Oram JF. The Tangier disease gene product ABC1 controls the cellular apolipoprotein-mediated lipid removal pathway.  J Clin Invest. 1999;  104 R25-R31
    CrossrefPubMedGoogle Scholar
  • 88 Choudhury RP, Rong JX, Trogan E, Elmalem VI, Dansky HM, Breslow JL, Witztum JL, Fallon JT, Fisher EA. High-density lipoproteins retard the progression of atherosclerosis and favorably remodel lesions without suppressing indices of inflammation or oxidation.  Arterioscler Thromb Vasc Biol. 2004;  24 1904-1909
    PubMedGoogle Scholar
  • 89 Accad M, Smith S, Newland D, Sanan D, King JL, Linton M, Fazio S, Farese JR. Massive zanthomatosis and altered composition of atherosclerotic lesions in hyperlipidemic mice lacking acyl CoA:cholesterol acyltransferase 1.  J Clin Invest. 2000;  105 711-719
    PubMedGoogle Scholar
  • 90 Yagyu H, Kitamine T, Osuga J, Tozawa R, Chen Z, Kaji Y, Oka T, Perrey S, Tamura Y, Ohashi K, Okazaki H, Yahagi N, Shionoiri F, Iizuka Y, Harada K, Shimano H, Yamashita H, Gotoda T, Yamada N, Ishibashi S. Absence of ACAT-1 attenuates atherosclerosis but causes dry eye and cutaneous xanthomatosis in mice with congenital hyperlipidemia.  J Biol Chem. 2000;  275 21324-21330
    CrossrefPubMedGoogle Scholar
  • 91 Zwarts KY, Clee SM, Zwinderman AH, Engert JC, Singaraja R, Loubser O, James E, Roomp K, Hudson TJ, Jukema JW, Kastelein JJP, Hayden MR. ABCA1 regulatory variants influence coronary artery disease independent of effects on plasma lipid levels.  Clin Genet. 2002;  61 115-125
    CrossrefPubMedGoogle Scholar
  • 92 Chawla A, Boisvert WA, Lee CH, Laffitte BA, Barak Y, Joseph SB, Liao D, Nagy L, Edwards PA, Curtiss LK, Evans RM, Tontonoz P. A PPAR gamma-LXR-ABCA1 pathway in macrophages is involved in cholesterol efflux and atherogenesis.  Mol Cell. 2001;  7 161-171
    CrossrefPubMedGoogle Scholar
  • 93 Repa JJ, Turley SD, Lobaccaro JA, Medina J, Li L, Lustig K, Shan B, Heyman RA, Dietschy JM, Mangelsdorf DJ. Regulation of absorption and ABC1-mediated efflux of cholesterol by RXR heterodimers.  Science. 2000;  289 1524-1529
    CrossrefPubMedGoogle Scholar
  • 94 Ricote M, Valledor AF, Glass CK. Decoding transcriptional programs regulated by PPARs and LXRs in the macrophage: effects on lipid homeostasis, inflammation, and atherosclerosis.  Arterioscler Thromb Vasc Biol. 2004;  24 230-239
    PubMedGoogle Scholar
  • 95 Linton MF, Fazio S. Macrophages, inflammation, and atherosclerosis.  Int J Obes Relat Metab Disord. 2003;  27 ((Suppl 3)) S35-S40
    CrossrefPubMedGoogle Scholar
  • 96 O'Brien KD, Vuletic S, McDonald TO, Wolfbauer G, Lewis K, Tu AY, Marcovina S, Wight TN, Chait A, Albers JJ. Cell-associated and extracellular phospholipid transfer protein in human coronary atherosclerosis.  Circulation. 2003;  108 270-274
    CrossrefPubMedGoogle Scholar
  • 97 Griendling KK, Minieri CA, Ollerenshaw JD, Alexander RW. Angiotensin II stimulates NADH and NADPH oxidase activity in cultured vascular smooth muscle cells.  Circ Res. 1994;  74 1141-1148
    CrossrefPubMedGoogle Scholar
  • 98 Huraux C, Makita T, Kurz S, Yamaguchi K, Szlam F, Tarpey MM, Wilcox JN, Harrison DG, Levy JH. Superoxide production, risk factors, and endothelium-dependent relaxations in human internal mammary arteries.  Circulation. 1999;  99 53-59
    PubMedGoogle Scholar
  • 99 Zhang H, Schmeisser A, Garlichs CD, Plotze K, Damme U, Mugge A, Daniel WG. Angiotensin II-induced superoxide anion generation in human vascular endothelial cells: role of membrane-bound NADH-/NADPH-oxidases.  Cardiovasc Res. 1999;  44 215-222
    CrossrefPubMedGoogle Scholar
  • 100 Ogawa S, Glass CK. Factor XIIIA (cross)links AT1 receptors to atherosclerosis.  Cell. 2004;  119 313-314
    CrossrefPubMedGoogle Scholar
  • 101 Vaughan DE, Lazos SA, Tong K. Angiotensin II regulates the expression of plasminogen activator inhibitor-1 in cultured endothelial cells.  J Clin Invest. 1995;  95 995-1001
    CrossrefPubMedGoogle Scholar
  • 102 Ridker PM, Gaboury CL, Conlin PR, Seely EW, Williams GH, Vaughan DE. Stimulation of plasminogen activator inhibitor in vivo by infusion of angiotensin II. Evidence of a potential interaction between the renin-angiotensin system and fibrinolytic function.  Circulation. 1993;  87 1969-1973
    PubMedGoogle Scholar
  • 103 Brown NJ, Agirbasli MA, Williams GH, Litchfield WR, Vaughan DE. Effect of activation and inhibition of the renin-angiotensin system on plasma PAI-1.  Hypertension. 1998;  32 965-977
    CrossrefPubMedGoogle Scholar
  • 104 Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. The Heart Outcomes Prevention Evaluation Study Investigators. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on death from cardiovascular causes, myocardial infarction, and stroke in high-risk patients.  N Engl J Med. 2000;  342 145-153
    CrossrefPubMedGoogle Scholar
  • 105 Nickenig G. Central role of the AT(1)-receptor in atherosclerosis.  J Hum Hypertens. 2002;  16 ((Suppl 3)) S26-S33
    PubMedGoogle Scholar
  • 106 Henrion D, Kubis N, Levy B. Physiological and pathophysiological functions of the AT2 subtype receptor of angiotensin II from large arteries to the microcirculation.  Hypertension. 2001;  38 1150-1157
    PubMedGoogle Scholar
  • 107 Barger AC, Beeuwkes R, Lainet L, Silverman KJ. Hypothesis: vasa vasorum and neovascularization of human coronary arteries.  N Engl J Med. 1984;  310 175-177
    CrossrefPubMedGoogle Scholar
  • 108 Moulton KS, Heller E, Konerding MA, Flynn E, Palinski W, Folkman J. Angiogenesis inhibitors endostatin or TNP-470 reduce intimal neovascularization and plaque growth in apolipoprotein E-deficient mice.  Circulation. 1999;  99 1726-1732
    PubMedGoogle Scholar
  • 109 Bornstein P. Thrombospondins: structure and regulation of expression.  FASEB J. 1992;  6 3290-3299
    PubMedGoogle Scholar
  • 110 Silverstein RL, Nachman RL. Angiogenesis and Atherosclerosis The Mandate Broadens.  Circulation. 1999;  100 783-785
    PubMedGoogle Scholar
  • 111 Stary HC. The Development of Calcium Deposits in Atherosclerotic Lesions and Their Persistence After Lipid Regression.  Am J Cardiol. 2001;  88 ((Suppl)) 16E-19E
    PubMedGoogle Scholar
  • 112 Paulsson G, Zhou X, Tornquist E, Hansson GK. Oligoclonal T cell expansions in atherosclerotic lesions of apolipoprotein E-deficient mice.  Arterioscler Thromb Vasc Biol. 2000;  20 10-17
    PubMedGoogle Scholar
  • 113 Zieske AW, Malcom GT, Strong JP. Natural history and risk factors of atherosclerosis in children and youth: the PDAY study.  Pediatr Pathol Mol Med. 2002;  21 213-237
    PubMedGoogle Scholar
  • 114 Vijayagopal P, Glancy DL. Macrophages stimulate cholesteryl ester accumulation in cocultured smooth muscle cells incubated with lipoprotein-proteoglycan complex.  Arterioscler Thromb Vasc Biol. 1996;  16 1112-1121
    PubMedGoogle Scholar
  • 115 Stein GS, Lian JB. Molecular mechanisms mediating proliferation/differentiation interrelationships during progressive development of the osteoblast phenotype.  Endocr Rev. 1993;  14 424-442
    CrossrefPubMedGoogle Scholar
  • 116 Bostrom K, Demer LL. Regulatory mechanisms in vascular calcification.  Crit Rev Eukaryot Gene Expr. 2000;  12 151-158
    PubMedGoogle Scholar
  • 117 Hungerford JE, Little CD. Developmental biology of the vascular smooth muscle cell: building a multilayered vessel wall.  J Vasc Res. 1999;  36 2-27
    CrossrefPubMedGoogle Scholar
  • 118 Bostrom K, Watson KE, Horn S, Wortham C, Herman IM, Demer LL. Bone morphogenetic protein expression in human atherosclerotic lesions.  J Clin Invest. 1993;  91 1800-1809
    PubMedGoogle Scholar
  • 119 Bostrom K. Insights into the Mechanism of Vascular Calcification.  Am J Cardiol. 2001;  88 ((Suppl)) 20E-22E
    PubMedGoogle Scholar
  • 120 Humphries SE, Martin S, Cooper J, Miller G. Interaction between smoking and the stromelysin-1 (MMP3) gene 5A/6A promoter polymorphism and risk of coronary heart disease in healthy men.  Ann Hum Genet. 2002;  66 343-352
    CrossrefPubMedGoogle Scholar
  • 121 Liu J, Sukhova GK, Sun JS, Xu WH, Libby P, Shi GP. Lysosomal cysteine proteases in atherosclerosis.  Arterioscler Thromb Vasc Biol. 2004;  24 1359-1366
    PubMedGoogle Scholar
  • 122 Dollery CM, Owen CA, Sukhova GK, Krettek A, Shapiro SD, Libby P. Neutrophil elastase in human atherosclerotic plaques: production by macrophages.  Circulation. 2003;  107 2829-2836
    CrossrefPubMedGoogle Scholar
  • 123 Carmeliet P. Proteinases in cardiovascular aneurysms and rupture: targets for therapy?.  J Clin Invest. 2000;  105 1519-1520
    PubMedGoogle Scholar
  • 124 Sugiyama S, Kugiyama K, Aikawa M, Nakamura S, Ogawa H, Libby P. Hypochlorous acid, a macrophage product, induces endothelial apoptosis and tissue factor expression: involvement of myeloperoxidase-mediated oxidant in plaque erosion and thrombogenesis.  Arterioscler Thromb Vasc Biol. 2004;  24 1309-1314
    PubMedGoogle Scholar
  • 125 Davies MJ. The pathophysiology of acute coronary syndxromes.  Heart. 2000;  83 361-366
    CrossrefPubMedGoogle Scholar
  • 126 Davies M. Stability and instability: two faces of coronary atherosclerosis. The Paul Dudley White Lecture 1995.  Circulation. 1996;  94 2013-2020
    PubMedGoogle Scholar
  • 127 Glass CK, Witztum JL. Atherosclerosis The Road Ahead.  Cell. 2001;  104 503-516
    CrossrefPubMedGoogle Scholar
  • 128 Cines DB, Pollak ES, Buck CA, Loscalzo J, Zimmerman GA, McEver RP, Pober JS, Wick TM, Konkle BA, Schwartz BS, Barnathan ES, McCrae KR, Hug BA, Schmidt AM, Stern DM. Endothelial cells in physiology and in the pathophysiology of vascular disorders.  Blood. 1998;  91 3527-3561
    PubMedGoogle Scholar
  • 129 Brownlee M. The pathobiology of diabetic complications: a unifying mechanism.  Diabetes. 2005;  54 1615-1625
    CrossrefPubMedGoogle Scholar
  • 130 Schrijvers BF, De Vriese AS, Flyvbjerg A. From hyperglycemia to diabetic kidney disease: the role of metabolic, hemodynamic, intracellular factors and growth factors/cytokines.  Endocr Rev. 2004;  25 971-1010
    CrossrefPubMedGoogle Scholar
  • 131 Wang R, Kudo M, Yokoyama M, Asano G. Roles of advanced glycation endproducts (AGE) and receptor for AGE on vascular smooth muscle cell growth.  EMBO J. 2004;  23 4096-4105
    CrossrefPubMedGoogle Scholar
  • 132 Stitt AW, Frizzell N, Thorpe SR. Advanced glycation and advanced lipoxidation: possible role in initiation and progression of diabetic retinopathy.  Curr Pharm Des. 2004;  10 3349-3360
    CrossrefPubMedGoogle Scholar
  • 133 Stevens FJ. Amyloid formation: an emulation of matrix protein assembly?.  Amyloid. 2004;  11 232-244
    PubMedGoogle Scholar
  • 134 He Z, King GL. Microvascular complications of diabetes.  Endocrinol Metab Clin North Am. 2004;  33 215-238
    CrossrefPubMedGoogle Scholar
  • 135 Yamagishi S, Imaizumi T. Diabetic vascular complications: pathophysiology, biochemical basis and potential therapeutic strategy.  Curr Pharm Des. 2005;  11 2279-2299
    CrossrefPubMedGoogle Scholar
  • 136 The Diabetes Control and Complications Trial Research Group . The effect of intensive treatment of diabeteson the development and progression of long-term complications in insulin-dependent diabetes mellitus.  N Engl J Med. 1993;  329 977-986
    Google Scholar
  • 137 UK Prospective Diabetes Group (UKPDS) . Intensive blood-glucose control with sulphonulureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes. (UKPDS 33).  Lancet. 1998;  352 837-853
    CrossrefPubMedGoogle Scholar
  • 138 Assert R, Scherk G, Bumbure A, Pirags V, Schatz H, Pfeiffer AF. Regulation of protein kinase C by short term hyperglycemia in human platelets in vivo and in vitro.  Diabetologia. 2001;  44 188-195
    CrossrefPubMedGoogle Scholar
  • 139 Nishikawa T, Edelstein D, Xu XL, Yamagishi S, Matsumura T, Kaneda Y, Yorek MA, Beebe D, Oates PJ, Hammes HP, Giardino I, Brownlee M. Normalizing mitochondrial superoxide production blocks three pathways of hyperglycemic damage.  Nature. 2000;  404 787-790
    CrossrefPubMedGoogle Scholar
  • 140 Kamiya H, Nakamura J, Hamada Y, Nakashima E, Naruse K, Kato K, Yasuda Y, Hotta N. Polyol pathway and protein kinase C activity of rat Schwannoma cells.  Diabetes Metab Res Rev. 2003;  19 131-139
    CrossrefPubMedGoogle Scholar
  • 141 Sheetz MJ, King L. Molecular understanding of hyperglycemia's adverse effects for diabetic complications.  JAMA. 2002;  288 2579-2588
    CrossrefPubMedGoogle Scholar
  • 142 Rask-Madsen C, King GL. Proatherosclerotic mechanisms involving protein kinase C in diabetes and insulin resistance.  Arterioscler Thromb Vasc Biol. 2005;  25 487-496
    PubMedGoogle Scholar
  • 143 Kim JK, Fillmore JJ, Sunshine MJ, Albrecht B, Higashimori T, Kim DW, Liu ZX, Soos TJ, Cline GW, O'Brien WR, Littman DR, Shulman GI. PKC-theta knockout mice are protected from fat-induced insulin resistance.  J Clin Invest. 2004;  114 823-827
    CrossrefPubMedGoogle Scholar
  • 144 Verma S, Anderson TJ. The most commonly asked questions about endothelial function in cardiology.  Cardiol Rev. 2001;  9 250-252
    PubMedGoogle Scholar
  • 145 Johnstone MT, Creager SJ, Scales KM, Cusco JA, Lee BK, Creager MA. Impaired endothelium-dependent vasodilation in patients with insulin-dependent diabetes mellitus. Impaired endothelium-dependent vasodilation in patients with insulin-dependent diabetes mellitus.  Circulation. 1993;  88 2510-2516
    PubMedGoogle Scholar
  • 146 De Vriese AS, Verbeuren TJ, Van de Voorde J, Lameire NH, Vanhoutte PM. Endothelial dysfunction in diabetes.  Br J Pharmacol. 2000;  130 963-974
    CrossrefPubMedGoogle Scholar
  • 147 Rosen P, Nawroth PP, King G, Moller W, Tritschler HJ, Packer L. The role of oxidative stress in the onset and progression of diabetes and its complications: a summary of a Congress Series sponsored by UNESCO-MCBN, the American Diabetes Association and the German Diabetes Society.  Diabetes Metab Res Rev. 2001;  17 189-212
    CrossrefPubMedGoogle Scholar
  • 148 Creager MA, Luscher TF, Cosentino F, Beckman JA. Diabetes and vascular disease: pathophysiology, clinical consequences, and medical therapy: Part I.  Circulation. 2003;  108 1527-1532
    CrossrefPubMedGoogle Scholar
  • 149 Vlassara H, Cai W, Crandall J, Goldberg T, Oberstein R, Dardaine V, Peppa M, Rayfield EJ. Inflammatory mediators are induced by dietary glycotoxins, a major risk factor for diabetic angiopathy.  Proc Natl Acad Sci USA. 2002;  99 15596-15601 , Erratum in: Proc Natl Acad Sci U S A 2003; 100: 763
    CrossrefPubMedGoogle Scholar
  • 150 Berg TJ, Dahl-Jorgensen K, Torjesen PA, Hanssen KF. Increased serum levels of advanced glycation end products (AGEs) in children and adolescents with IDDM.  Diabetes Care. 1997;  20 1006-1008
    CrossrefPubMedGoogle Scholar
  • 151 Chiarelli F, de Martino M, Mezzetti A, Catino M, Morgese G, Cuccurullo F, Verrotti A. Advanced glycation end products in children and adolescents with diabetes: relation to glycemic control and early microvascular complications.  J Pediatr. 1999;  134 486-491
    PubMedGoogle Scholar
  • 152 Miyazaki A, Nakayama H, Horiuchi S. Scavenger receptors that recognize advanced glycation end products.  Trends Cardiovasc Med. 2002;  12 258-262
    CrossrefPubMedGoogle Scholar
  • 153 Cipollone F, Iezzi A, Fazia M, Zucchelli M, Pini B, Cuccurullo C, De Cesare D, De Blasis G, Muraro R, Bei R, Chiarelli F, Schmidt AM, Cuccurullo F, Mezzetti A. The receptor RAGE as a progression factor amplifying arachidonate-dependent inflammatory and proteolytic response in human atherosclerotic plaques: role of glycemic control.  Circulation. 2003;  108 1070-1077
    CrossrefPubMedGoogle Scholar
  • 154 Bierhaus A, Humpert PM, Morcos M, Wendt T, Chavakis T, Arnold B, Stern DM, Nawroth PP. Understanding RAGE, the receptor for advanced glycation end products.  J Mol Med. 2005;  83 876-886
    CrossrefPubMedGoogle Scholar
  • 155 Vlassara H, Palace MR. Diabetes and advanced glycation endproducts.  J Intern Med. 2002;  251 87-101
    CrossrefPubMedGoogle Scholar
  • 156 Libby P, Plutzky J. Editorial, Diabetic Macrovascular Disease The Glucose Paradox?.  Circulation. 2002;  106 2760-2763
    CrossrefPubMedGoogle Scholar
  • 157 Aronson D. Cross-linking of glycated collagen in the pathogenesis of arterial and myocardial stiffening of aging and diabetes.  J Hypertens. 2003;  21 3-12
    CrossrefPubMedGoogle Scholar
  • 158 Reddy GK. AGE-related cross-linking of collagen is associated with aortic wall matrix stiffness in the pathogenesis of drug-induced diabetes in rats.  Microvasc Res. 2004;  68 132-142
    CrossrefPubMedGoogle Scholar
  • 159 Stitt AW, He C, Vlassara H. Characterization of the advanced glycation end-product receptor complex in human vascular endothelial cells.  Biochem Biophys Res Commun. 1999;  256 549-556
    CrossrefPubMedGoogle Scholar
  • 160 McFarlane S, Glenn JV, Lichanska AM, Simpson DA, Stitt AW. Characterisation of the advanced glycation endproduct receptor complex in the retinal pigment epithelium.  Br J Ophthalmol. 2005;  89 107-112
    CrossrefPubMedGoogle Scholar
  • 161 Bucciarelli LG, Wendt T, Rong L, Lalla E, Hofmann MA, Goova MT, Taguchi A, Yan SF, Yan SD, Stern DM, Schmidt AM. RAGE is a multiligand receptor of the immunoglobulin superfamily: implications for homeostasis and chronic disease.  Cell Mol Life Sci. 2002;  59 1117-1128
    CrossrefPubMedGoogle Scholar
  • 162 Yonekura H, Yamamoto Y, Sakurai S, Watanabe T, Yamamoto H. Roles of the receptor for advanced glycation endproducts in diabetes-induced vascular injury.  J Pharmacol Sci. 2005;  97 305-311
    CrossrefPubMedGoogle Scholar
  • 163 Ramasamy R, Vannucci SJ, Yan SS, Herold K, Yan SF, Schmidt AM. Advanced glycation end products and RAGE: a common thread in aging, diabetes, neurodegeneration, and inflammation.  Glycobiology. 2005;  15 16-28
    CrossrefPubMedGoogle Scholar
  • 164 Alikhani Z, Alikhani M, Boyd CM, Nagao K, Trackman PC, Graves DT. Advanced glycation end products enhance expression of pro-apoptotic genes and stimulate fibroblast apoptosis through cytoplasmic and mitochondrial pathways.  J Biol Chem. 2005;  280 12087-12095
    PubMedGoogle Scholar
  • 165 Sims TJ, Rasmussen LM, Oxlund H, Bailey AJ. The role of glycation cross-links in diabetic vascular stiffening.  Diabetologia. 1996;  39 964-951
    PubMedGoogle Scholar
  • 166 Schmidt AM, Stern D. Atheroclerosis and diabetes.  Curr Atheroscler Rep. 2000;  2 430-436
    CrossrefPubMedGoogle Scholar
  • 167 Wendt TM, Tanji N, Guo J, Kislinger TR, Qu W, Lu Y, Bucciarelli LG, Rong LL, Moser B, Markowitz GS, Stein G, Bierhaus A, Liliensiek B, Arnold B, Nawroth PP, Stern DM, D'Agati VD, Schmidt AM. RAGE drives the development of glomerulosclerosis and implicates podocyte activation in the pathogenesis of diabetic nephropathy.  Am J Pathol. 2003;  162 1123-1137
    CrossrefPubMedGoogle Scholar
  • 168 Bucciarelli LG, Wendt T, Qu W, Lu Y, Lalla E, Rong LL, Goova MT, Moser B, Kislinger T, Lee DC, Kashyap Y, Stern DM, Schmidt AM. RAGE blockade stabilizes established atherosclerosis in diabetic apolipoprotein E-null mice.  Circulation. 2002;  106 2827-2835
    CrossrefPubMedGoogle Scholar
  • 169 Yan SF, Ramasamy R, Naka Y, Schmidt AM. Glycation, inflammation, and RAGE: a scaffold for the macrovascular complications of diabetes and beyond.  Circ Res. 2003;  93 1159-1169
    CrossrefPubMedGoogle Scholar
  • 170 Mukhopadhyay S, Mukherjee TK. Bridging advanced glycation end product, receptor for advanced glycation end product and nitric oxide with hormonal replacement/estrogen therapy in healthy versus diabetic postmenopausal women: a perspective.  Biochim Biophys Acta. 2005;  1745 145-155
    PubMedGoogle Scholar
  • 171 Stitt AW, He C, Friedman S, Scher L, Rossi P, Ong L, Founds H, Li YM, Bucala R, Vlassara H. Elevated AGE-modified ApoB in sera of euglycemic, normolipidemic patients with atherosclerosis: relationship to tissue AGEs.  Mol Med. 1997;  3 617-627
    PubMedGoogle Scholar
  • 172 Binder CJ, Chang M-K, Shaw PX, Miller YI, Hartvigsen K, Dewan A, Witztum JL. Innate and acquired immunity in atherogenesis.  Nat Med. 2002;  8 1218-1226
    PubMedGoogle Scholar
  • 173 Hussain MJ, Peakman M, Gallati H, Lo SS, Hawa M, Viberti GC, Watkins PJ, Leslie RD, Vergani D. Elevated serum levels of macrophage-derived cytokines precede and accompany the onset of IDDM.  Diabetologia. 1996;  39 60-69
    PubMedGoogle Scholar
  • 174 Uemura S, Matsushita H, Li W, Glassford AJ, Asagami T, Lee KH, Harrison DG, Tsao PS. Diabetes mellitus enhances vascular matrix metalloproteinase activity: role of oxidative stress.  Circ Res. 2001;  88 1291-1298
    CrossrefPubMedGoogle Scholar
  • 175 Schneider DJ. Abnormalities of coagulation, platelet function, and fibrinolysis associated with syndromes of insulin resistance.  Coron Artery Dis. 2005;  16 473-476
    CrossrefPubMedGoogle Scholar
  • 176 Li Y, Woo V, Bose R. Platelet hyperactivity and abnormal Ca(2+) homeostasis in diabetes mellitus.  Am J Physiol Heart Circ Physiol. 2001;  280 H1480-H1489
    PubMedGoogle Scholar
  • 177 Ceriello A, Giugliano D, Quatraro A, Dello Russo P, Torella R. Blood glucose may condition factor VII levels in diabetic and normal subjects.  Diabetologia. 1988;  31 889-891
    PubMedGoogle Scholar
  • 178 Ceriello A, Giugliano D, Quatraro A, Marchi E, Barbanti M, Lefebvre P. Evidence for a hyperglycemia-dependent decrease of antithrombin III-thrombin complex formation in humans.  Diabetologia. 1990;  33 163-167
    CrossrefPubMedGoogle Scholar
  • 179 Ceriello A, Giacomello R, Stel G, Motz E, Taboga C, Tonutti L, Pirisi M, Falleti E, Bartoli E. Hyperglycemia-induced thrombin formation in diabetes. The possible role of oxidative stress.  Diabetes. 1995;  44 924-928
    PubMedGoogle Scholar
  • 180 Moreno PR, Fuster V. New aspects in the pathogenesis of diabetic atherothrombosis.  J Am Coll Cardiol. 2004;  44 2293-2300
    CrossrefPubMedGoogle Scholar
  • 181 Nordt TK, Bode C. Impaired endogenous fibrinolysis in diabetes mellitus.  Semin Thromb Hemost. 2000;  26 495-501
    Article in Thieme ConnectPubMedGoogle Scholar
  • 182 Carr ME. Diabetes mellitus: a hyperocoagulable state.  J Diabetes Complications. 2001;  15 44-54
    CrossrefPubMedGoogle Scholar
  • 183 Nathan DM, Cleary PA, Backlund JY, Genuth SM, Lachin JM, Orchard TJ, Raskin P, Zinman B. Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes.  N Engl J Med. 2005;  353 2643-2653
    CrossrefPubMedGoogle Scholar

Correspondence

Francesco ChiarelliM.D., Ph.D. 

Department of Pediatrics·University of Chieti

Via dei Vestini 5

66100 Chieti

Italy

Phone: +39/0871/35 80 15

Fax: +39/0871/57 48 31

Email: chiarelli@unich.it

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