Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1996 Jul 1;98(1):24–29. doi: 10.1172/JCI118771

Vascular dysfunction in monkeys with diet-induced hyperhomocyst(e)inemia.

S R Lentz 1, C G Sobey 1, D J Piegors 1, M Y Bhopatkar 1, F M Faraci 1, M R Malinow 1, D D Heistad 1
PMCID: PMC507396  PMID: 8690798

Abstract

Elevated plasma homocyst(e)ine may predispose to complications of vascular disease. Homocysteine alters vasomotor regulatory and anticoagulant properties of cultured vascular endothelial cells, but little is known about effects of hyperhomocyst(e)inemia on vascular function in vivo. We tested the hypothesis that diet-induced moderate hyperhomocyst(e)inemia is associated with vascular dysfunction in cynomolgus monkeys. Plasma homocyst(e)ine increased from 4.O +/- O.2 microM when monkeys were fed normal diet to 10.6 +/- 2.6 microM when they were fed modified diet (mean +/- SE; P = 0.02). Vasomotor responses were assessed in vivo by quantitative angiography and Doppler measurement of blood flow velocity. In response to activation of platelets by intraarterial infusion of collagen, blood flow to the leg decreased by 42 +/- 9% in monkeys fed modified diet, compared with 14 +/- 11% in monkeys fed normal diet (P = 0.008), Responses of resistance vessels to the endothelium-dependent vasodilators acetylcholine and ADP were markedly impaired in hyperhomocyst(e)inemic monkeys, which suggests that increased vasoconstriction in response to collagen may be caused by decreased vasodilator responsiveness to platelet-generated ADP. Relaxation to acetylcholine and, to a lesser extent, nitroprusside, was impaired ex vivo in carotid arteries from monkeys fed modified diet. Thrombomodulin anticoagulant activity in aorta decreased by 34 +/- 15% in hyperhomocyst(e)inemic monkeys (P = 0.03). We conclude that diet-induced moderate hyperhomocyst(e)inemia is associated with altered vascular function.

Full Text

The Full Text of this article is available as a PDF (207.4 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Benzuly K. H., Padgett R. C., Kaul S., Piegors D. J., Armstrong M. L., Heistad D. D. Functional improvement precedes structural regression of atherosclerosis. Circulation. 1994 Apr;89(4):1810–1818. doi: 10.1161/01.cir.89.4.1810. [DOI] [PubMed] [Google Scholar]
  2. Boushey C. J., Beresford S. A., Omenn G. S., Motulsky A. G. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease. Probable benefits of increasing folic acid intakes. JAMA. 1995 Oct 4;274(13):1049–1057. doi: 10.1001/jama.1995.03530130055028. [DOI] [PubMed] [Google Scholar]
  3. CLAUSS A. Gerinnungsphysiologische Schnellmethode zur Bestimmung des Fibrinogens. Acta Haematol. 1957 Apr;17(4):237–246. doi: 10.1159/000205234. [DOI] [PubMed] [Google Scholar]
  4. Celermajer D. S., Sorensen K., Ryalls M., Robinson J., Thomas O., Leonard J. V., Deanfield J. E. Impaired endothelial function occurs in the systemic arteries of children with homozygous homocystinuria but not in their heterozygous parents. J Am Coll Cardiol. 1993 Sep;22(3):854–858. doi: 10.1016/0735-1097(93)90203-d. [DOI] [PubMed] [Google Scholar]
  5. Creager M. A., Cooke J. P., Mendelsohn M. E., Gallagher S. J., Coleman S. M., Loscalzo J., Dzau V. J. Impaired vasodilation of forearm resistance vessels in hypercholesterolemic humans. J Clin Invest. 1990 Jul;86(1):228–234. doi: 10.1172/JCI114688. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Faraci F. M., Orgren K., Heistad D. D. Impaired relaxation of the carotid artery during activation of ATP-sensitive potassium channels in atherosclerotic monkeys. Stroke. 1994 Jan;25(1):178–182. doi: 10.1161/01.str.25.1.178. [DOI] [PubMed] [Google Scholar]
  7. Freiman P. C., Mitchell G. G., Heistad D. D., Armstrong M. L., Harrison D. G. Atherosclerosis impairs endothelium-dependent vascular relaxation to acetylcholine and thrombin in primates. Circ Res. 1986 Jun;58(6):783–789. doi: 10.1161/01.res.58.6.783. [DOI] [PubMed] [Google Scholar]
  8. Fryer R. H., Wilson B. D., Gubler D. B., Fitzgerald L. A., Rodgers G. M. Homocysteine, a risk factor for premature vascular disease and thrombosis, induces tissue factor activity in endothelial cells. Arterioscler Thromb. 1993 Sep;13(9):1327–1333. doi: 10.1161/01.atv.13.9.1327. [DOI] [PubMed] [Google Scholar]
  9. Hajjar K. A. Homocysteine-induced modulation of tissue plasminogen activator binding to its endothelial cell membrane receptor. J Clin Invest. 1993 Jun;91(6):2873–2879. doi: 10.1172/JCI116532. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Harrison D. G., Armstrong M. L., Freiman P. C., Heistad D. D. Restoration of endothelium-dependent relaxation by dietary treatment of atherosclerosis. J Clin Invest. 1987 Dec;80(6):1808–1811. doi: 10.1172/JCI113276. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Houston D. S., Shepherd J. T., Vanhoutte P. M. Aggregating human platelets cause direct contraction and endothelium-dependent relaxation of isolated canine coronary arteries. Role of serotonin, thromboxane A2, and adenine nucleotides. J Clin Invest. 1986 Aug;78(2):539–544. doi: 10.1172/JCI112606. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Jacobsen D. W. Cardiovascular disorders (risk assessment). Anal Chem. 1993 Jun 15;65(12):367R–373R. doi: 10.1021/ac00060a600. [DOI] [PubMed] [Google Scholar]
  13. Kang S. S., Wong P. W., Malinow M. R. Hyperhomocyst(e)inemia as a risk factor for occlusive vascular disease. Annu Rev Nutr. 1992;12:279–298. doi: 10.1146/annurev.nu.12.070192.001431. [DOI] [PubMed] [Google Scholar]
  14. Kaul S., Heistad D. D., Mügge A., Armstrong M. L., Piegors D. J., Lopez J. A. Vascular responses to platelet activation in normal and atherosclerotic primates in vivo. Arterioscler Thromb. 1991 Nov-Dec;11(6):1745–1751. doi: 10.1161/01.atv.11.6.1745. [DOI] [PubMed] [Google Scholar]
  15. Lentz S. R., Sadler J. E. Homocysteine inhibits von Willebrand factor processing and secretion by preventing transport from the endoplasmic reticulum. Blood. 1993 Feb 1;81(3):683–689. [PubMed] [Google Scholar]
  16. Lentz S. R., Sadler J. E. Inhibition of thrombomodulin surface expression and protein C activation by the thrombogenic agent homocysteine. J Clin Invest. 1991 Dec;88(6):1906–1914. doi: 10.1172/JCI115514. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Ludmer P. L., Selwyn A. P., Shook T. L., Wayne R. R., Mudge G. H., Alexander R. W., Ganz P. Paradoxical vasoconstriction induced by acetylcholine in atherosclerotic coronary arteries. N Engl J Med. 1986 Oct 23;315(17):1046–1051. doi: 10.1056/NEJM198610233151702. [DOI] [PubMed] [Google Scholar]
  18. Malinow M. R., Kang S. S., Taylor L. M., Wong P. W., Coull B., Inahara T., Mukerjee D., Sexton G., Upson B. Prevalence of hyperhomocyst(e)inemia in patients with peripheral arterial occlusive disease. Circulation. 1989 Jun;79(6):1180–1188. doi: 10.1161/01.cir.79.6.1180. [DOI] [PubMed] [Google Scholar]
  19. Mudd S. H., Levy H. L. Plasma homocyst(e)ine or homocysteine? N Engl J Med. 1995 Aug 3;333(5):325–325. doi: 10.1056/NEJM199508033330520. [DOI] [PubMed] [Google Scholar]
  20. Mudd S. H., Skovby F., Levy H. L., Pettigrew K. D., Wilcken B., Pyeritz R. E., Andria G., Boers G. H., Bromberg I. L., Cerone R. The natural history of homocystinuria due to cystathionine beta-synthase deficiency. Am J Hum Genet. 1985 Jan;37(1):1–31. [PMC free article] [PubMed] [Google Scholar]
  21. Raife T. J., Lager D. J., Madison K. C., Piette W. W., Howard E. J., Sturm M. T., Chen Y., Lentz S. R. Thrombomodulin expression by human keratinocytes. Induction of cofactor activity during epidermal differentiation. J Clin Invest. 1994 Apr;93(4):1846–1851. doi: 10.1172/JCI117171. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Rodgers G. M., Conn M. T. Homocysteine, an atherogenic stimulus, reduces protein C activation by arterial and venous endothelial cells. Blood. 1990 Feb 15;75(4):895–901. [PubMed] [Google Scholar]
  23. Rodgers G. M., Kane W. H. Activation of endogenous factor V by a homocysteine-induced vascular endothelial cell activator. J Clin Invest. 1986 Jun;77(6):1909–1916. doi: 10.1172/JCI112519. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Selhub J., Jacques P. F., Bostom A. G., D'Agostino R. B., Wilson P. W., Belanger A. J., O'Leary D. H., Wolf P. A., Schaefer E. J., Rosenberg I. H. Association between plasma homocysteine concentrations and extracranial carotid-artery stenosis. N Engl J Med. 1995 Feb 2;332(5):286–291. doi: 10.1056/NEJM199502023320502. [DOI] [PubMed] [Google Scholar]
  25. Selhub J., Jacques P. F., Wilson P. W., Rush D., Rosenberg I. H. Vitamin status and intake as primary determinants of homocysteinemia in an elderly population. JAMA. 1993 Dec 8;270(22):2693–2698. doi: 10.1001/jama.1993.03510220049033. [DOI] [PubMed] [Google Scholar]
  26. Smolin L. A., Schneider J. A. Measurement of total plasma cysteamine using high-performance liquid chromatography with electrochemical detection. Anal Biochem. 1988 Feb 1;168(2):374–379. doi: 10.1016/0003-2697(88)90332-6. [DOI] [PubMed] [Google Scholar]
  27. Stamler J. S., Osborne J. A., Jaraki O., Rabbani L. E., Mullins M., Singel D., Loscalzo J. Adverse vascular effects of homocysteine are modulated by endothelium-derived relaxing factor and related oxides of nitrogen. J Clin Invest. 1993 Jan;91(1):308–318. doi: 10.1172/JCI116187. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Stampfer M. J., Malinow M. R. Can lowering homocysteine levels reduce cardiovascular risk? N Engl J Med. 1995 Feb 2;332(5):328–329. doi: 10.1056/NEJM199502023320511. [DOI] [PubMed] [Google Scholar]
  29. Starkebaum G., Harlan J. M. Endothelial cell injury due to copper-catalyzed hydrogen peroxide generation from homocysteine. J Clin Invest. 1986 Apr;77(4):1370–1376. doi: 10.1172/JCI112442. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Willerson J. T., Hillis L. D., Winniford M., Buja L. M. Speculation regarding mechanisms responsible for acute ischemic heart disease syndromes. J Am Coll Cardiol. 1986 Jul;8(1):245–250. doi: 10.1016/s0735-1097(86)80121-8. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES