The synthetic pentasaccharide fondaparinux prevents coronary microvascular injury and myocardial dysfunction in the ischemic heart

Summary

Fondaparinux is a synthetic pentasaccharide with powerful anticoagulant properties, which may also reduce ischemia-reperfusion (I/R) injury in vivo.However,the relative contributions of the anticoagulant and anti-inflammatory activities of fondaparinux to the observed protection are unknown.To address this issue, a crystalloid-perfused heart model was used to assess potential effects of fondaparinux on IR-induced heart injury in the absence of blood. Fondaparinux protects the ischemic myocardium independently of its haemostasis effects. Fondaparinux improved post ischemic myocardial contractile performance and tissue damage. These beneficial effects of fondaparinux may be related to the observed reduction in IR-induced oxidative stress and endothelial activation. In addition, fondaparinux altered NADPH oxidase activity and phosphorylated extracellular signal-regulated kinase (ERK) 1/2, suggesting activation of survival signaling pathways. The present study provides novel information by demonstrating that fondaparinux can attenuate inflammatory responses and oxidative stress in connection with IR heart injury. These findings could represent a potential therapeutic strategy for the prevention of myocardial dysfunction.

Keywords

Ischemia reperfusion - heart - reactive oxygen species - heparin

^* These authors contributed equally to this work.

• References

• 1 Weitz JI. Emerging anticoagulants for the treatment of venous thromboembolism. Thromb Haemost 2006; 96: 274-284.
• 2 Bassand JP, Richard-Lordereau I, Cadroy Y. Efficacy and safety of fondaparinux in patients with acute coronary syndromes. Expert Rev Cardiovasc Ther 2007; 05: 1013-1026.
• 3 Cornet AD, Smit EG, Beishuizen A, Groeneveld AB. The role of heparin and allied compounds in the treatment of sepsis. Thromb Haemost 2007; 98: 579-586.
• 4 Frank RD, Schabbauer G, Holscher T. et al. The synthetic pentasaccharide fondaparinux reduces coagulation, inflammation and neutrophil accumulation in kidney ischemia-reperfusion injury. J Thromb Hae-most 2005; 03: 531-540.
• 5 Olanders K, Borjesson A, Zhao X. et al. Effects of anticoagulant treatment on intestinal ischaemia and reperfusion injury in rats. Acta Anaesthesiol Scand 2005; 49: 517-524.
• 6 Yellon DM, Hausenloy DJ. Myocardial reperfusion injury. N Engl J Med 2007; 357: 1121-1135.
• 7 Frank RD, Holscher T, Schabbauer G. et al. A non-anticoagulant synthetic pentasaccharide reduces inflammation in a murine model of kidney ischemia-reperfusion injury. Thromb Haemost 2006; 96: 802-806.
• 8 Turpie AG. Fondaparinux: a Factor Xa inhibitor for antithrombotic therapy. Expert Opin Pharmacother 2004; 05: 1373-1384.
• 9 Rubio-Gayosso I, Platts SH, Duling BR. Reactive oxygen species mediate modification of glycocalyx during ischemia-reperfusion injury. Am J Physiol Heart Circ Physiol 2006; 290: H2247-H2256.
• 10 Favory R, Lancel S, Tissier S. et al. Myocardial dysfunction and potential cardiac hypoxia in rats induced by carbon monoxide inhalation. Am J Respir Crit Care Med 2006; 174: 320-325.
• 11 Chilian WM, DeFily DV. Methodological approaches used for the study of the coronary microcirculation in situ. Blood Vessels 1991; 28: 236-244.
• 12 Marechal X, Favory R, Joulin O. et al. Endothelial glycocalyx damage during endotoxemia coincides with microcirculatory dysfunction and vascular oxidative stress. Shock 2008; 29: 572-576.
• 13 Rota C, Chignell CF, Mason RP. Evidence for free radical formation during the oxidation of 2’-7’-dich-lorofluorescin to the fluorescent dye 2’-7’-dichlorofluorescein by horseradish peroxidase: possible implications for oxidative stress measurements. Free Radic Biol Med 1999; 27: 873-881.
• 14 Guo Z, Xia Z, Jiang J. et al. Downregulation of NADPH oxidase, antioxidant enzymes, and inflammatory markers in the heart of streptozotocin-induced diabetic rats by N-acetyl-L-cysteine. Am J Physiol Heart Circ Physiol 2007; 292: H1728-H1736.
• 15 Bleeke T, Zhang H, Madamanchi N. et al. Catecholamine-induced vascular wall growth is dependent on generation of reactive oxygen species. Circ Res 2004; 94: 37-45.
• 16 Ludwig RJ, Alban S, Bistrian R. et al. The ability of different forms of heparins to suppress P-selectin function in vitro correlates to their inhibitory capacity on bloodborne metastasis in vivo. Thromb Haemost 2006; 95: 535-540.
• 17 Reitsma S, Slaaf DW, Vink H. et al. The endothelial glycocalyx: composition, functions, and visualization. Pflugers Arch 2007; 454: 345-359.
• 18 Rehm M, Bruegger D, Christ F. et al. Shedding of the endothelial glycocalyx in patients undergoing major vascular surgery with global and regional ischemia. Circulation 2007; 116: 1896-1906.
• 19 Mulivor AW, Lipowsky HH. Inflammation- and ischemia-induced shedding of venular glycocalyx. Am J Physiol Heart Circ Physiol. 2004 286. H1672-H1680.
• 20 Berry CE, Hare JM. Xanthine oxidoreductase and cardiovascular disease: molecular mechanisms and pathophysiological implications. J Physiol 2004; 555: 589-606.
• 21 Yokoyama Y, Beckman JS, Beckman TK. et al. Circulating xanthine oxidase: potential mediator of ischemic injury. Am J Physiol 1990; 258: G564-G570.
• 22 Hawes EM, Watts JA. Xanthine oxidase/dehydrogenase release following ischemia in isolated rat hearts. Am J Cardiovasc Pathol 1993; 04: 326-335.
• 23 Radi R, Rubbo H, Bush K. et al. Xanthine oxidase binding to glycosaminoglycans: kinetics and super-oxide dismutase interactions of immobilized xanthine oxidase-heparin complexes. Arch Biochem Biophys 1997; 339: 125-135.
• 24 Cave AC, Brewer AC, Narayanapanicker A. et al. NADPH oxidases in cardiovascular health and disease. Antioxid Redox Signal 2006; 08: 691-728.
• 25 Hoffmeyer MR, Jones SP, Ross CR, Sharp B, Grisham MB, Laroux FS. et al. Myocardial ischemia/reperfusion injury in NADPH oxidase-deficient mice. Circ Res 2000; 87: 812-817.
• 26 Bell RM, Cave AC, Johar S. et al. Pivotal role of NOX-2-containing NADPH oxidase in early ischemic preconditioning. FA SEB J 2005; 19: 2037-2039.
• 27 Córdoba M, Mora N, Beconi MT. Respiratory burst and NAD(P)H oxidase activity are involved in capacitation of cryopreserved bovine spermatozoa. Theriogenology 2006; 65: 882-892.
• 28 Sabri A, Hughie HH, Lucchesi PA. Regulation of hypertrophic and apoptotic signaling pathways by reactive oxygen species in cardiac myocytes. Antioxid Redox Signal 2003; 05: 731-740.
• 29 Nediani C, Borchi E, Giordano C. et al. NADPH oxidase-dependent redox signaling in human heart failure: relationship between the left and right ventricle. J Mol Cell Cardiol 2007; 42: 826-834.
• 30 Qin F, Shite J, Liang CS. Antioxidants attenuate myocyte apoptosis and improve cardiac function in CHF: association with changes in MAPK pathways. Am J Physiol Heart Circ Physiol 2003; 285: H822-H832.
• 31 Junttila MR, Li SP, Westermarck J. Phosphatase-mediated crosstalk between MAPK signaling pathways in the regulation of cell survival. FASEB J 2008; 22: 954-965.
• 32 Muslin AJ. Role of raf proteins in cardiac hypertrophy and cardiomyocyte survival. Trends Cardiovasc Med 2005; 15: 225-229.