Heme oxygenase-1 inducer hemin prevents vascular thrombosis

Nicolas Desbuards; Gaël Y. Rochefort; Deborah Schlecht; Marie-Christine Machet; Jean-Michel Halimi; Véronique Eder; Jean-Marc Hyvelin; Daniel Antier

doi:10.1160/TH06-12-0717

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2007; 98(03): 614-620
DOI: 10.1160/TH06-12-0717

Blood Coagulation, Fibrinolysis and Cellular Haemostasis

Schattauer GmbH

Heme oxygenase-1 inducer hemin prevents vascular thrombosis

Nicolas Desbuards

¹LABPART – EA 3852 – IFR135 – Université François Rabelais, Tours Cedex 1, France

,

Gaël Y. Rochefort

¹LABPART – EA 3852 – IFR135 – Université François Rabelais, Tours Cedex 1, France

,

Deborah Schlecht

¹LABPART – EA 3852 – IFR135 – Université François Rabelais, Tours Cedex 1, France

,

Marie-Christine Machet

¹LABPART – EA 3852 – IFR135 – Université François Rabelais, Tours Cedex 1, France

,

Jean-Michel Halimi

¹LABPART – EA 3852 – IFR135 – Université François Rabelais, Tours Cedex 1, France

,

Véronique Eder

¹LABPART – EA 3852 – IFR135 – Université François Rabelais, Tours Cedex 1, France

,

Jean-Marc Hyvelin

¹LABPART – EA 3852 – IFR135 – Université François Rabelais, Tours Cedex 1, France

,

Daniel Antier

¹LABPART – EA 3852 – IFR135 – Université François Rabelais, Tours Cedex 1, France

› Institutsangaben

Abstract

Summary

Hemin is a heme oxygenase-1 (HO-1) inducer which provides endogenous carbon monoxide known for playing roles in cell proliferation,inflammation or aggregation process. The objective of the current study was to examine the effect of prophylactic treatment with hemin in a thrombosis vascular model. Three groups of Wistar rats, control (n=6), hemin (n=6) and hemin+HO-1 inhibitor (n=6), were used for this study. Hemintreated animals received hemin (50 mg/kg/d; I.P.) for seven days and HO-1 inhibitor group received hemin at the same dose and SnPP IX (60 mg/kg/d; I.P.). All animals were exposed to electric stimulation of the left carotid according to Kawasaki’s procedure to induce reproducible thrombus formation. The hemin treatment did not induce blood pressure disturbance. Effects of hemin on vascular thrombosis were quantified by histopathology and its influence on haemostasis was assessed by measuring prothrombin time (PT), activated partial thromboplastin time (APTT) and blood parameters at the end of treatment. The HO-1 mRNA and protein level variation were also checked out. Results showed that chronic treatment with hemin significantly (p<0.01) reduced the vascular occlusion degree when compared to control and hemin SnPP groups with 7.2 ± 4.6 vs. 71.1 ± 14.7 and 74.0 ± 8.8%, respectively. Moreover, we observed significant (p<0.05) perturbations of blood parameters in hemintreated and hemin-SnPP treated rats. Interestingly, hemin treatment did not significantly increase both PT and APTT. Finally, the HO-1 mRNA and protein levels were increased in hemintreated carotid artery. In conclusion, hemin by inducing HO-1 expression may be a preventive agent against clinical disorders associated to an increased risk of thrombosis events and may limit haemorrhagic risks.

Keywords

Hemin - vascular thrombosis - rat

Volltext

Referenzen

References
1 Leizorovicz A, Mismetti P. Preventing venous thromboembolism in medical patients. Circulation 2004; 110 (24) (Suppl. 01) IV13-19.
2 Feres F, Costa Jr., JR, Abizaid A. Very late thrombosis after drug-eluting stents. Catheter Cardiovasc Interv 2006; 68: 83-88.
3 Park DW, Park SW, Park KH. et al. Frequency of and risk factors for stent thrombosis after drug-eluting stent implantation during long-term follow-up. Am J Cardiol 2006; 98: 352-356.
4 Andtbacka RH, Babiera G, Singletary SE. et al. Incidence and prevention of venous thromboembolism in patients undergoing breast cancer surgery and treated according to clinical pathways. Ann Surg 2006; 243: 96-101.
5 Levine MN, Raskob G, Beyth RJ. et al. Hemorrhagic complications of anticoagulant treatment: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126 (03) Suppl 287S-310S.
6 Kroll MH, Hellums JD, McIntire LV. et al. Platelets and shear stress. Blood 1996; 88: 1525-1541.
7 Jackson SP, Nesbitt WS, Kulkarni S. Signaling events underlying thrombus formation. J Thromb Haemost 2003; 1: 1602-1612.
8 Gawaz M. Role of platelets in coronary thrombosis and reperfusion of ischemic myocardium. Cardiovasc Res 2004; 61: 498-511.
9 Weyrich AS, Lindemann S, Zimmerman GA. The evolving role of platelets in inflammation. J Thromb Haemost 2003; 1: 1897-1905.
10 Kikuchi G, Yoshida T, Noguchi M. Heme oxygenase and heme degradation. Biochem Biophys Res Commun 2005; 338: 558-567.
11 Maines MD. The heme oxygenase system: a regulator of second messenger gases. Annu Rev Pharmacol Toxicol 1997; 37: 517-554.
12 Morita T. Heme oxygenase and atherosclerosis. Arterioscler Thromb Vasc Biol 2005; 25: 1786-1795.
13 Otterbein LE, Bach FH, Alam J. et al. Carbon monoxide has anti-inflammatory effects involving the mitogen- activated protein kinase pathway. Nat Med 2000; 6: 422-428.
14 Wagener FA, Volk HD, Willis D. et al. Different faces of the heme-heme oxygenase system in inflammation. Pharmacol Rev 2003; 55: 551-571.
15 Wunder C, Potter RF. The heme oxygenase system: its role in liver inflammation. Curr Drug Targets Cardiovasc Haematol Disord 2003; 3: 199-208.
16 Duckers HJ, Boehm M, True AL. et al. Heme oxygenase-1 protects against vascular constriction and proliferation. Nat Med 2001; 7: 693-698.
17 Morita T, Mitsialis SA, Koike H. et al. Carbon monoxide controls the proliferation of hypoxic vascular smooth muscle cells. J Biol Chem 1997; 272: 32804-32809.
18 Peyton KJ, Reyna SV, Chapman GB. et al. Heme oxygenase-1-derived carbon monoxide is an autocrine inhibitor of vascular smooth muscle cell growth. Blood 2002; 99: 4443-4448.
19 Tulis DA, Keswani AN, Peyton KJ. et al. Local administration of carbon monoxide inhibits neointima formation in balloon injured rat carotid arteries. Cell Mol Biol (Noisy-le-grand) 2005; 51: 441-446.
20 Brouard S, Otterbein LE, Anrather J. et al. Carbon monoxide generated by heme oxygenase 1 suppresses endothelial cell apoptosis. J Exp Med 2000; 192: 1015-1026.
21 Brouard S, Berberat PO, Tobiasch E. et al. Heme oxygenase-1-derived carbon monoxide requires the activation of transcription factor NF-kappa B to protect endothelial cells from tumor necrosis factor-alpha-mediated apoptosis. J Biol Chem 2002; 277: 17950-17961.
22 Silva G, Cunha A, Gregoire IP. et al. The antiapoptotic effect of heme oxygenase-1 in endothelial cells involves the degradation of p38 alpha MAPK isoform. J Immunol 2006; 177: 1894-1903.
23 Mansouri A, Perry CA. Alteration of platelet aggregation by cigarette smoke and carbon monoxide. Thromb Haemost 1982; 48: 286-288.
24 Brune B, Ullrich V. Inhibition of platelet aggregation by carbon monoxide is mediated by activation of guanylate cyclase. Mol Pharmacol 1987; 32: 497-504.
25 Ryter SW, Alam J, Choi AM. Heme oxygenase- 1/carbon monoxide: from basic science to therapeutic applications. Physiol Rev 2006; 86: 583-650.
26 Kawasaki T, Sato K, Hirayama F. et al. Effect of a synthetic factor Xa inhibitor, YM-60828, on blood vessel patency in combination with a thrombolytic agent and on blood loss from the operation site in a rat model of arterial thrombosis. Thromb Haemost 1998; 79: 859-864.
27 Braggins PE, Trakshel GM, Kutty RK. et al. Characterization of two heme oxygenase isoforms in rat spleen: comparison with the hematin-induced and constitutive isoforms of the liver. Biochem Biophys Res Commun 1986; 141: 528-533.
28 Shamloul R, Wang R. Monitoring circulatory heme level in hemin therapy for lowering blood pressure in rats. Cell Mol Biol (Noisy-le-grand) 2005; 51: 507-512.
29 Rochefort GY, Libgot R, Desbuards N. et al. Effect of the heme oxygenase inducer hemin on blood haemostasis measured by high-frequency ultrasound. Clin Exp Pharmacol P. 2007 ; in press.
30 Ishikawa K, Sugawara D, Wang X. et al. Heme oxygenase-1 inhibits atherosclerotic lesion formation in ldl-receptor knockout mice. Circ Res 2001; 88: 506-512.
31 Lindenblatt N, Bordel R, Schareck W. et al. Vascular heme oxygenase-1 induction suppresses microvascular thrombus formation in vivo. Arterioscler Thromb Vasc Biol 2004; 24: 601-606.
32 Song R, Mahidhara RS, Zhou Z. et al. Carbon monoxide inhibits T lymphocyte proliferation via caspasedependent pathway. J Immunol 2004; 172: 1220-1226.
33 Pae HO, Oh GS, Choi BM. et al. Carbon monoxide produced by heme oxygenase-1 suppresses T cell proliferation via inhibition of IL-2 production. J Immunol 2004; 172: 4744-4751.
34 Suzuki S, Kassell NF, Lee KS. Hemin activation of an inducible isoform of nitric oxide synthase in vascular smooth-muscle cells. J Neurosurg 1995; 83: 862-866.
35 Kong D, Melo LG, Mangi AA. et al. Enhanced inhibition of neointimal hyperplasia by genetically engineered endothelial progenitor cells. Circulation 2004; 109: 1769-1775.
36 Jacob SW, Herschler R. Pharmacology of DMSO. Cryobiology 1986; 23: 14-27.
37 Saeed SA, Karimi SJ, Suria A. Differential effects of dimethyl sulfoxide on human platelet aggregation and arachidonic acid metabolism. Biochem Med Metab Biol 1988; 40: 143-150.
38 Gorog P, Kovacs IB. Antiarthritic and antithrombotic effects of topically applied dimethyl sulfoxide. Ann NY Acad Sci 1975; 243: 91-97.
39 Peng L, Mundada L, Stomel JM. et al. Induction of heme oxygenase-1 expression inhibits platelet-dependent thrombosis. Antioxid Redox Signal 2004; 6: 729-735.
40 Amer J, Fibach E. Oxidative status of platelets in normal and thalassemic blood. Thromb Haemost 2004; 92: 1052-1059.
41 Glueck R, Green D, Cohen I. et al. Hematin: unique effects of hemostasis. Blood 1983; 61: 243-249.
42 Volin L, Rasi V, Vahtera E. et al. Heme arginate: effects on hemostasis. Blood 1988; 71: 625-628.