Download PDF
Thromb Haemost 1997; 78(05): 1332-1337
DOI: 10.1055/s-0038-1665406
Review Article
Schattauer GmbH Stuttgart

Endothelial Marker Proteins in Hyperhomocysteinemia

Sylvia C de Jong
1   The Institute for Cardiovascular Research, Vrije Universiteit, Amsterdam, The Netherlands
2   The Department of Surgery, Division of Vascular Surgery, Amsterdam, The Netherlands
,
Coen D A Stehouwer
1   The Institute for Cardiovascular Research, Vrije Universiteit, Amsterdam, The Netherlands
3   The Department of Internal Medicine, Academisch Ziekenhuis Vrije Universiteit, Amsterdam, The Netherlands
,
Michiel van den Berg
1   The Institute for Cardiovascular Research, Vrije Universiteit, Amsterdam, The Netherlands
2   The Department of Surgery, Division of Vascular Surgery, Amsterdam, The Netherlands
,
Ulrich M Vischer
4   The Division de Biochimie Clinique, CMU, Geneva, Switzerland
,
Jan A Rauwerda
1   The Institute for Cardiovascular Research, Vrije Universiteit, Amsterdam, The Netherlands
2   The Department of Surgery, Division of Vascular Surgery, Amsterdam, The Netherlands
,
Jef J Emeis
5   The Gaubius Laboratory TNO-PG, Leiden, The Netherlands
› Author Affiliations
Further Information

Publication History

Received 27 1997

Accepted after resubmission 07 July 1997

Publication Date:
12 July 2018 (online)

Also available at
  PDF Download  Permissions and Reprints

Summary

Hyperhomocysteinemia is associated with severe, premature atherosclerosis and thromboembolism. The mechanisms involved in the atherogenic and thrombotic complications of hyperhomocysteinemia are not understood. It has been suggested that hyperhomocysteinemia predisposes to atherosclerosis by injuring the vascular endothelium. Whether hyperhomocysteinemia is independently associated with changed endothelial function, either in the absence or the presence of clinically manifest atherosclerotic disease, is, however, not known. Therefore we investigated, both in patients with peripheral arterial occlusive disease and in healthy individuals, whether plasma protein markers of endothelial function differed between subjects with, and subjects without hyperhomocysteinemia. We studied 80 individuals under the age of 56 years: healthy individuals with (n = 20) and without (n = 20) hyperhomocysteinemia and patients with peripheral arterial occlusive disease with (n = 20) and without (n = 20) hyperhomocysteinemia. The following endothelium-derived proteins were measured as markers of endothelial cell function: von Willebrand factor (vWf) and von Willebrand factor propeptide (vWf: Agll), tissue-type plasminogen activator (tPA), plasminogen activator inhibitor-1 (PAI-1), cellular fibronectin (cFN) and thrombomodulin ™. In addition we assessed C-reactive protein (CRP). vWf, vWf: Agll, tPA and CRP were significantly higher in the patients with peripheral arterial occlusive disease than in the healthy individuals. No differences in marker protein plasma levels were found between individuals with, and those without hyperhomocysteinemia, apart from vWf, which was significantly raised in hyperhomocysteinemic as compared to normohomocysteinemic patients. We did not find any evidence for an independent association between hyperhomocysteinemia and protein markers of endothelial cell function in healthy subjects.

 

  • References

  • 1 Stampfer MJ, Malinow MR, Willett WC, Newcomer LM, Upson BUllman, Tishler PV, Hennekens CH. A prospective study of plasma homocyst(e)ine and risk of myocardial infarction in US physicians. JAMA 1992; 268: 877-881
    CrossrefPubMedSearch in Google Scholar
  • 2 Perry IJ, Refsum H, Morris RW, Ebrahim SB, Ueland PM, Schaper AG. Prospective study of serum total homocysteine concentration and risk of stroke in middle-aged British men. Lancet 1995; 346: 1395-1398
    CrossrefPubMedSearch in Google Scholar
  • 3 Den HeijerM, Koster T, Blom HJ, Bos GMJ, Briët E, Reitsma PH, Vanden-broucke JP, Rosendaal FR. Hyperhomocysteinemia as a risk factor for deep-vein thrombosis. N Engl J Med 1996; 334: 759-762
    CrossrefPubMedSearch in Google Scholar
  • 4 Den Heijer M, Blom HJ, Gerrits WBJ, Rosendaal FR, Haak HL, Wijermans PW, Bos GMJ. Is hyperhomocysteinemia a risk factor for recurrent venous thrombosis?. Lancet 1995; 345: 882-885
    CrossrefPubMedSearch in Google Scholar
  • 5 Wall TW, Harlan JM, Harker LA, Striker GE. Homocysteine-induced endothelial cell injury in vitro: a model for the study of vascular injury. Thromb Res 1980; 18: 113-121
    CrossrefPubMedSearch in Google Scholar
  • 6 De GrootPG, Willems C, Boers GHJ, Gonsalves MD, Van AkenWG, Van MourikJA. Endothelial cell dysfunction in homocystinuria. Eur J Clin Invest 1983; 13: 405-410
    CrossrefPubMedSearch in Google Scholar
  • 7 Rolland PH, Friggi A, Barlatier A, Piquet P, Latrille V, Faye MM, Guillou J, Charpiot P, Bodard H, Ghiringhelli O, Calaf R, Luccioni R, Carçon D. Hyperhomocysteinemia-induced vascular damage in the minipig; captopril- hydrochlorothiazide combination prevents elastic alterations. Circulation 1995; 91: 1161-1174
    CrossrefPubMedSearch in Google Scholar
  • 8 Lentz SR, Sobey CG, Piegors DJ, Bhopatkar MY, Farad FM, Malinow MR, Heistad DD. Vascular dysfunction in monkeys with diet-induced hyperhomocyst(e)inemia. J Clin Invest 1996; 98: 24-29
    CrossrefPubMedSearch in Google Scholar
  • 9 Van denBerg M, Stehouwer CDA, Boers GHJ, Rauwerda JA, Kluft C. Arterial disease in hyperhomocysteinaemia and the effect of treatment; a pilot study. Fibrinolysis 1994; 8 (Suppl. 2) 88-90
    PubMedSearch in Google Scholar
  • 10 Van denBergM, Boers GHJ, Franken DG, Blom HJ, van KampGJ, Jacobs C, Rauwerda JA, Kluft C, Stehouwer CDA. Hyperhomocysteinaemia and endothelial dysfunction in young patients with peripheral arterial occlusive disease. Eur J Clin Invest 1995; 25: 176-181
    CrossrefPubMedSearch in Google Scholar
  • 11 Ridker PM, Hennekens CH, Stampfer MJ, Manson JAE, Vaughan DE. Prospective study of endogenous tissue plasminogen activator and risk of stroke. Lancet 1994; 343: 940-943
    CrossrefPubMedSearch in Google Scholar
  • 12 Ridker PM, Vaughan DE, Stampfer MJ, Manson JE, Hennekens CH. Endogenous tissue-type plasminogeen activator and risk of myocardial infarction. Lancet 1993; 341: 1165-1168
    CrossrefPubMedSearch in Google Scholar
  • 13 Hamsten A, Walldius G, Szamosi A, Blomback M, De FaireU, Dahle G, Landou C, Wiman B. Plasminogen activator inhibitor in plasma: risk factor for recurrent myocardial infarction. Lancet 1987; 02: 03-09
    PubMedSearch in Google Scholar
  • 14 Thompson SG, Kienast J, Pyke SDM, Haverkate F, Van deLooJCW. Hemostatic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris. N Engl J Med 1995; 332: 635-641
    CrossrefPubMedSearch in Google Scholar
  • 15 Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens C. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med 1997; 336: 973-979
    CrossrefPubMedSearch in Google Scholar
  • 16 Juhan-Vague I, Pyke SDM, Alessi MC, Jespersen J, Haverkate F, Thompson SG. Fibrinolytic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris. Circulation 1996; 94: 2057-2063
    CrossrefPubMedSearch in Google Scholar
  • 17 Haverkate F, Thompson SG, Pyke SDM, Gallimore JR, Pepys MB. Production of C-reactive protein and risk of coronary events in stable and unstable angina. Lancet 1997; 349: 462-466
    CrossrefPubMedSearch in Google Scholar
  • 18 Kuller LH, Tracy RP, Shaten J, Meilahn EN. Relation of C-reactive protein and coronary heart disease in the MRFIT nested case-control study. Am J Epidemiol 1996; 144: 537-547
    CrossrefPubMedSearch in Google Scholar
  • 19 Van denBerg M, Stehouwer CDA, Bierdrager E, Rauwerda JA. Plasma homocysteine and severity of atherosclerosis in young patients with lower-limb atherosclerotic disease. Arterioscler Thromb Vase Biol 1996; 16: 165-171
    CrossrefPubMedSearch in Google Scholar
  • 20 Rutherford RB, Flanigan DP, Gupta Sk, Johnston KW, Karmody A, Whittemore D, Baker JD, Ernst CB. Suggested standards for reports dealing with lower extremity ischemia. J Vase Surg 1986; 04: 80-94
    CrossrefPubMedSearch in Google Scholar
  • 21 Ubbink JB, Vermaak WJH, Bissbort S. Rapid high-performance liquid chromatographic assay for total homocysteine levels in human serum. J Chromatogr 1991; 565: 441-446
    CrossrefPubMedSearch in Google Scholar
  • 22 Ingerslev JA. A sensitive ELISA for von Willebrand factor (vWF:Ag). Scand J Clin Lab Invest 1987; 47: 143-149
    CrossrefPubMedSearch in Google Scholar
  • 23 Tranquille N, Emeis JJ. The simultaneous acute release of tissue-type plasminogen activator and von Willebrand factor in the perfused rat hindleg region. Thromb Haemost 1990; 63: 454-458
    Thieme ConnectPubMedSearch in Google Scholar
  • 24 Stehouwer CDA, Nauta JJP, Zeldenrust GC, Hackeng WHL, Donker AJM, den OttolanderGJH. Urinary albumin excretion, cardiovascular disease, and endothelial dysfunction in non-insulin-dependent diabetes mellitus. Lancet 1992; 340: 319-323
    CrossrefPubMedSearch in Google Scholar
  • 25 Vischer UM, Ingerslev J, Wollheim CB, Mestries JC, Tsakiris DA, Haefeli WE, Kruithof EKO. Acute von Willebrand factor secretion from the endothelium in vivo: assessment through plasma propeptide (vWF: Agll) levels. Thromb Haemost 1997; 77: 387-393
    Thieme ConnectPubMedSearch in Google Scholar
  • 26 Camemolla B, Borsi L, Zardi L, Owens RJ, Baralle FE. Localization of the cellular-fibronectin-specific epitope recognized by the monoclonal anti body IST-9 using fusion proteins expressed in E.coli. FEBS Letters 1987; 215: 269-273
    CrossrefPubMedSearch in Google Scholar
  • 27 Myrup B, de MaatM, Rossing P, Gram J, Kluft C, Jespersen J. Elevated fibrinogen and the relation to acute phase response in diabetic nephropathy. Thromb Haemost 1996; 81: 485-490
    PubMedSearch in Google Scholar
  • 28 Haverkate F, Thompson SG, Duckert F. Haemostasis factors in angina pectoris; relation to gender, age and acute-phase reaction. Thromb Haemost 1995; 73: 561-567
    Thieme ConnectPubMedSearch in Google Scholar
  • 29 Harker LA, Ross R, Slichter SJ, Scott CR. Homocystine-induced arteriosclerosis. The role of endothelial cell injury and platelet response in its genesis. J Clin Invest 1976; 58: 731-741
    CrossrefPubMedSearch in Google Scholar
  • 30 Lubec B, Arbeiter K, Hoeger H, Lubec G. Increased cyclin dependent kinase in aortic tissue of rats fed homocysteine. Thromb Haemostas 1996; 75: 542-545
    PubMedSearch in Google Scholar
  • 31 McCully KS. Homocysteine theory of arteriosclerosis: development and current status. Atheroscler Rev 1983; 11: 157-246
    PubMedSearch in Google Scholar
  • 32 Tawakol A, Omland T, Gerhard M, Wu JT, Creager MA. Hyperhomocyst(e)inemia is associated with impaired endothelium-dependent vasodilation in humans. Circulation 1997; 95: 1119-1121
    CrossrefPubMedSearch in Google Scholar
  • 33 Celermajer DS, Sorensen KE, Gooch VM, Spiegelhalter DJ, Miller OI, Sullivan ID, Lloyd JK, Deanfield JE. Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis. Lancet 1992; 340: 1111-1115
    CrossrefPubMedSearch in Google Scholar
  • 34 Solerte SB, Piovella F, Viola C, Schianca GC, Gamba G, Fioravanti M, Ferrari E. Plasma fibronectin, von Willebrand factor antigen, and blood rheology. Association with diabetec microvascular disease. Acta Diabetol Lat 1985; 22: 239-246
    CrossrefPubMedSearch in Google Scholar
  • 35 Blann AD, Maxwell SRJ, Burrows G, Miller P. Antioxidants, von Willebrand factor and endothelial cell injury in hypercholesterolaemia and vascular disease. Atherosclerosis 1995; 116: 191-198
    CrossrefPubMedSearch in Google Scholar
  • 36 Stroes ESG, Koomans HA, de BruinTWA, Rabelink TJ. Vascular function in the forearm of hypercholesterolaemic patients off and on lipid-lowering medication. Lancet 1995; 346: 467-471
    CrossrefPubMedSearch in Google Scholar