PDF herunterladen
Thromb Haemost 2001; 85(04): 724-729
DOI: 10.1055/s-0037-1615659
Review Articles
Schattauer GmbH

N-acetyl-cysteine Reduces Neointimal Thickening and Procoagulant Activity after Balloon-induced Injury in Abdominal Aortae of New Zealand White Rabbits

Giorgio Ghigliotti  
1   Department of Cardiology, University of Genova, Genova, Department of Pharmacology, University of Genova, Genova, Italy
,
Eugenio Mereto  
,
Paul R. Eisenberg
2   Lilly Research Laboratories, Indianapolis, IN, USA
,
Antonietta Martelli
1   Department of Cardiology, University of Genova, Genova, Department of Pharmacology, University of Genova, Genova, Italy
,
Patrizia Orsi
1   Department of Cardiology, University of Genova, Genova, Department of Pharmacology, University of Genova, Genova, Italy
,
Daniela Sini
1   Department of Cardiology, University of Genova, Genova, Department of Pharmacology, University of Genova, Genova, Italy
,
Paolo Spallarossa
1   Department of Cardiology, University of Genova, Genova, Department of Pharmacology, University of Genova, Genova, Italy
› Institutsangaben
Weitere Informationen

Publikationsverlauf

Received 22. Februar 2001

Accepted after resubmission 06. November 2000

Publikationsdatum:
08. Dezember 2017 (online)

Auch verfügbar auf
    Lizenzen und Reprints

Summary

Background: Procoagulant activity and oxidative stress generated by balloon injury to normal vessels promote the migration of medial smooth muscle cells and their proliferation in the intima. We hypothesised that administering levo N-acetyl-cysteine (NAC) i.v. at the time of injury, and s.c. before and after injury would reduce neointimal formation 4 weeks later and would regulate procoagulant activity in vessels with neointima undergoing ballooning a second time. Methods and Results: at the time of injury rabbits received: NAC, unfractionated heparin (HEP) or both (NAC + HEP). Neointimal thickening at 28 days, calculated as the ratio between the intimal and medial area, was attenuated after NAC, HEP and NAC+HEP by 39%, 30% and 47% respectively when compared to untreated injured animals (CONTROLS) (p 0.05). At 28 days, bound thrombin activity and platelet adhesion 1 h after a repeated balloon injury decreased in animals receiving NAC, HEP and NAC+HEP by 54%, 63% and 64% for thrombin activity (p 0.05 vs CONTROLS), and by 56%, 66% and 75% respectively for 111Indium-platelet deposition (p 0.05 vs CONTROLS). Conclusions: NAC in-vivo was effective in reducing neointimal thickening and procoagulant response after balloon injury.

Keywords

Levo N-acetyl-cysteine - thrombin - tissue factor - neointima - rabbit

Giorgio Ghigliotti and Eugenio Mereto equally contributed to this study.


 

  • References

  • 1 Fuster V, Badimon L, Badimon J, Chesebro J. The pathogenesis of coronary artery disease and the acute coronary syndromes. N Eng J Med 1992; 326 (Suppl. 05) 310-8.
    CrossrefPubMedSuche in Google Scholar
  • 2 Gray A, Park P, Broekelmann T, Laurent G, Reeves J, Stenmark K, Mecham R. The mitogenic effects of the B beta chain of fibrinogen are mediated through cell surface calreticulin. J Biol Chem 1995; 270 (Suppl. 44) 26602-6.
    CrossrefPubMedSuche in Google Scholar
  • 3 Bar-Shavit R, Eldor A, Vlodavsky I. Binding of thrombin to subendothelial extracellular matrix. Protection and expression of functional properties. J Clin Invest 1989; 84: 1096-104.
    CrossrefPubMedSuche in Google Scholar
  • 4 Gasic G, Arenas C, Gasic T, Gasic G. Coagulation factors X, Xa and protein S as potent mitogens for cultured aortic smooth muscle cells. Proc Natl Acad Sci USA 1992; 89: 2317-20.
    CrossrefPubMedSuche in Google Scholar
  • 5 Libby P, Schwartz D, Brogi E, Tanaka H, Clinton S. A cascade model for restenosis. A special case of atherosclerosis progression. Circ 1992; 86 06 i1147-i1142.
    CrossrefPubMedSuche in Google Scholar
  • 6 Gawaz M, Brand K, Dickfeld T, Pogatsa-Murray G, Page S, Bogner C, Koch W, Schomig A, Neumann F. Platelets induce alterations of chemo-tactic and adhesive properties of endothelial cells mediated through an interleukin-1-dependent mechanism. Implications for atherogenesis. Atherosclerosis 2000; 148 (Suppl. 01) 75-85.
    CrossrefPubMedSuche in Google Scholar
  • 7 Tanaka H, Sukhova G, Swanson S, Clinton S, Ganz P, Cybulsky M, Libby P. Sustained activation of vascular cells and leukocytes in the rabbit aorta after balloon injury. Circulation 1993; 88 (Suppl. 04) 1788-803.
    CrossrefPubMedSuche in Google Scholar
  • 8 Laurindo F, da Luz P, Uint L, Rocha T, Jaeger R, Lopes E. Evidence for superoxide radical-dependent coronary vasospasm after angioplasty in intact dogs. Circulation 1991; 83: 1705-15.
    CrossrefPubMedSuche in Google Scholar
  • 9 Izzotti A, D’Agostini F, Bagnasco M, Scatolini L, Rovida A, Balansky R, Cesarone C, De Flora S. Chemoprevention of carcinogen-DNA adducts and chronic degenerative diseases. Cancer Res 1994; 54 Suppl. S 1994-8.
    PubMedSuche in Google Scholar
  • 10 Bellas R, Lee J, Sonenshein G. Expression of a constitutive NF-kappa B-like activity is essential for proliferation of cultured bovine vascular smooth muscle cells. J Clin Invest 1995; 96 (Suppl. 05) 2521-7.
    CrossrefPubMedSuche in Google Scholar
  • 11 Lee J, Kypreos K, Sonenshein G. Synchronization of cultured vascular smooth muscle cells following reversal of quiescence induced by treatment with the antioxidant N-acetylcysteine. Experimental Cell Research 1998; 239 (Suppl. 02) 447-53.
    CrossrefPubMedSuche in Google Scholar
  • 12 Stamler J, Mendelsohn M, Amarante P, Smick D, Andon N, Davies P, Cooke J, Loscalzo J. N-acetylcysteine potentiates platelet inhibition by endothelium-derived relaxing factor. Circ Res 1989; 65 (Suppl. 03) 789-95.
    CrossrefPubMedSuche in Google Scholar
  • 13 Speidel C, Eisenberg P, Ruf W, Edgington T, Abendschein D. Tissue factor mediates prolonged procoagulant activity on the luminal surface of balloon injured aortae in rabbits. Circulation 1995; 92 (Suppl. 11) 3323-30.
    CrossrefPubMedSuche in Google Scholar
  • 14 Ghigliotti G, Waissbluth A, Speidel C, Abendschein D, Eisenberg P. Prolonged activation of prothrombin on the vascular wall after arterial injury. Arterioscler Thromb Vasc Biol 1998; 18 (Suppl. 02) 250-7.
    CrossrefPubMedSuche in Google Scholar
  • 15 Borgstrom L, Kagedal B, Paulsen O. Pharmacokinetics of N-Acetylcysteine in Man. Eur J Clin Pharmacol 1986; 31: 217-22.
    CrossrefPubMedSuche in Google Scholar
  • 16 Pollman M, Hall J, Gibbons G. Determinants of Vascular Smooth Muscle Cell Apoptosis After Balloon Angioplasty Injury. Influence of Redox State and Cell Phenotype. Circ Res 1999; 84: 113-21.
    CrossrefPubMedSuche in Google Scholar
  • 17 Sedlak J, Lindsay R. Estimation of Total, Protein-bound, and Non-protein Sulphydryl Groups in Tissue with Ellman’s Reagent. Anal Biochem 1968; 25: 192-205.
    CrossrefPubMedSuche in Google Scholar
  • 18 Heaton W, Davis H, Welch M, Mathias C, Joist J, Sherman L, Siegel B. Indium-111: a New Radionuclide Label for Studying Human Platelet Kinetics. British Journal Haematol 1979; 42: 613-22.
    PubMedSuche in Google Scholar
  • 19 Clauss A. Gerinnungsphysiologische Schnellmethode zur Bestimmung des Fibrinogens. Acta Haematol 1957; 17: 237-45.
    CrossrefPubMedSuche in Google Scholar
  • 20 Clowes A, Karnovsky M. Suppression by heparin of smooth muscle cell proliferation in injured arteries. Nature (London) 1977; 265: 625-6.
    CrossrefPubMedSuche in Google Scholar
  • 21 Schwartz S, de Blois D, O’Brien E. The intima. Soil for atherosclerosis and restenosis. Circ Res 1995; 77 (Suppl. 03) 445-65.
    CrossrefPubMedSuche in Google Scholar
  • 22 Rao G, Katki K, Madamanchi N, Wu Y, Birrer M. JunB forms the majority of the AP-1 complex and is a target for redox regulation by receptor tyro-sine kinase and G protein-coupled receptor agonists in smooth muscle cells. J Biol Chem 1999; 274 (Suppl. 09) 6003-10.
    CrossrefPubMedSuche in Google Scholar
  • 23 Toborek M, Barger S, Mattson M, McClain C, Hennig B. Role of glutathione redox cycle in TNF-α-mediated endothelial cell dysfunction. Atherosclerosis 1995; 117: 179-88.
    CrossrefPubMedSuche in Google Scholar
  • 24 Aruoma O, Halliwell B, Hoey B, Butler J. The antioxidant action of N-acetylcysteine: its reaction with hydrogen peroxide, hydroxyl radical, superoxide, and hypochlorous acid. Free Radic Biol Med 1989; 6: 593-7.
    CrossrefPubMedSuche in Google Scholar
  • 25 Nunes G, Robinson K, Kalynych A, King S, Sgoutas D, Berk B. Vitamins C and E inhibit O2-production in the pig coronary artery. Circulation 1997; 96: 3593-601.
    CrossrefPubMedSuche in Google Scholar
  • 26 Hishikawa K, Oemar B, Yang Z, Luscher T. Pulsatile stretch stimulates superoxide production and activates nuclear factor kB in human coronary smooth muscle. Circ Res 1997; 81: 797-803.
    CrossrefPubMedSuche in Google Scholar
  • 27 Faruqi R, poptic E, Faruqi T, De La Motte C, DiCorleto P. Distinct mechanisms for N-acetylcysteine inhibition of cytokine-induced E-selectin and VCAM-1 expression. Am J Physiol 1997; 273 2 Pt 2 H817-26.
    PubMedSuche in Google Scholar
  • 28 Cotgreave I, Moldeus P, Schuppe I. The metabolism of N-acetylcysteine by human endothelial cells. Biochem Pharmacol 1991; 42 (Suppl. 01) 13-6.
    CrossrefPubMedSuche in Google Scholar
  • 29 Kingma JJ, Rouleau J. Effect of N-acetylcysteine on tissue necrosis during acute myocardial infarction in rabbits. Can J Cardiol 1989; 5 (Suppl. 06) 321-6.
    PubMedSuche in Google Scholar
  • 30 Zhang H, Spapen H, Nguyen D, Benlabed M, Buurman W, Vincent J. Protective effects of N-acetyl-L-cysteine in endotoxemia. Am J Physiol 1994; 266 5 Pt 2 H1746-54.
    PubMedSuche in Google Scholar
  • 31 Edelman E, Karnovsky M. Contrasting effects of the intermittent and continuous administration of heparin in experimental restenosis. Circulation 1994; 89 (Suppl. 02) 770-6.
    CrossrefPubMedSuche in Google Scholar
  • 32 Rogers C, Welt F, Karnovsky M, Edelman E. Monocyte Recruitment and Neointimal Hyperplasia in Rabbits. Coupled Inhibitory Effects of Heparin. Arterioscler Thromb Vasc Biol 1996; 16: 1312-8.
    CrossrefPubMedSuche in Google Scholar
  • 33 Rogers C, Karnovsky M, Edelman E. Inhibition of Experimental Neointimal Hyperplasia and Thrombosis Depends on the Type of Vascular Injury and the Site of Drug Administration. Circulation 1993; 88: 1215-21.
    CrossrefPubMedSuche in Google Scholar
  • 34 Asada Y, Hara S, Tsuneyoshi A, Hatakeyama K, Kisanuki A, Marutsuka K, Sato Y, Kamikubo Y, Sumiyoshi A. Fibrin-rich and platelet-rich thrombus formation on neointima: recombinant tissue factor pathway inhibitor prevents fibrin formation and neointimal development following repeated balloon injury of rabbit aorta. Thromb Haemost 1998; 80 (Suppl. 03) 506-11.
    Thieme ConnectPubMedSuche in Google Scholar
  • 35 Jorgensen L, Grothe A, Groves H, Kinlough-Rathbone R, Richardson M, Mustard J. Sequence of cellular responses in rabbit aortas following one and two injuries with a balloon catheter. Br J Exp Pathol 1988; 69 (Suppl. 04) 473-86.
    PubMedSuche in Google Scholar
  • 36 Stamler J, Cunningham M, Loscalzo J. Reduced thiols and the effect of intravenous nitroglycerin on platelet aggregation. Am J Cardiol 1988; 62 (Suppl. 07) 377-80.
    CrossrefPubMedSuche in Google Scholar
  • 37 Mollace V, Salvemini D, Sessa W, Vane J. Inhibition of human platelet aggregation by endothelium-derived relaxing factor, sodium nitroprusside or iloprost is potentiated by captopril and reduced thiols. J Pharmacol Exp Ther 1991; 258 (Suppl. 03) 820-3.
    PubMedSuche in Google Scholar
  • 38 Fingerle J, Johnson R, Clowes A, Majesky M, Reidy M. Role of platelets in smooth muscle cell proliferation and migration after vascular injury in rat carotid artery. Proc Natl Acad Sci 1989; 86: 8412-6.
    CrossrefPubMedSuche in Google Scholar
  • 39 Hatton M, Moar S, Richardson M. Deendothelialization in vivo initiates a thrombogenic reaction at the rabbit aorta surface: correlation of uptake of fibrinogen and antithrombin III with thrombin generation by the exposed subendothelium. Am J Path 1989; 135: 499-508.
    PubMedSuche in Google Scholar
  • 40 Groves H, Kinlough-Rathbone R, Richardson M, Jorgensen L, Moore S, Mustard J. Thrombin Generation and Fibrin Formation following Injury to Rabbit Neointima. Studies of Vessel Wall Reactivity and Platelet Survival. Lab Invest 1982; 46 (Suppl. 06) 605-12.
    PubMedSuche in Google Scholar
  • 41 Mann K. The coagulation explosion. Ann N Y Acad Sci 1994; 714: 265-9.
    CrossrefPubMedSuche in Google Scholar
  • 42 Spaet T, Stemerman M, Veith F, Lejnieks I. Intimal injury and regrowth in the rabbit aorta; medial smooth muscle cells as a source of neointima. Circ Res 1975; 36 (Suppl. 01) 58-70.
    CrossrefPubMedSuche in Google Scholar