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Cardiovascular Research 1995 30(6):965-974; doi:10.1016/S0008-6363(95)00157-3
© 1995 by European Society of Cardiology
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Copyright © 1995, European Society of Cardiology

Cardioprotection by liposome-conjugated sialyl Lewisx-oligosaccharide in myocardial ischaemia and reperfusion injury

Toyoaki Muroharaa, John Margiottaa, Laurie M. Phillipsb, James C. Paulsonb, Shawn DeFreesb, Samuel Zalipskyc, Luke S.S. Guoc and Allan M. Lefer*

aDepartment of Physiology, Jefferson Medical College, Thomas Jefferson University, 1020 Locust Street, Philadelphia, PA 19107, USA
bCytel Corporation, San Diego, CA 92121, USA
cLiposome Technology Inc., Menlo Park, CA 94025, USA

* Corresponding author. Tel: (+1-215) 955-7760, Fax: (+1-215) 955-2073.

Objectives. Selectins are important adhesion molecules which utilize a carbohydrate ligand such as sialyl Lewisx (SLex). Our objective was to study the effects of a liposome-conjugated SLex (Lipo-SLex) in myocardial ischaemia (MI) and reperfusion (R) injury in order to further clarify the actions of this carbohydrate. Methods. We studied the efficacy of Lipo-SLex in a feline model of MI (90 min) and R (270 min) injury in vivo. Lipo-SLex (400 µg SLex/kg, iv) was administered intravenously 10 min prior to R. We also utilized an in vitro system of neutrophil adherence to thrombin-stimulated coronary endothelium to validate the efficacy of Lipo-SLex. Results. Lipo-SLex significantly attenuated myocardial necrosis (8.6 ± 1.2 vs 29.5 ± 3.1% of area-at-risk, P < 0.01) and plasma creatine kinase activities (P < 0.01) compared to vehicle (liposome alone). Moreover, endothelium-dependent relaxation to acetylcholine and A23187 [GenBank] in ischaemic-reperfused coronary rings obtained from cats treated with Lipo-SLex was significantly preserved compared to cats given liposomes without SLex (P < 0.01). After reperfusion, ex vivo PMN adherence to ischaemic-reperfused coronary endothelium was significantly increased in vehicle-treated cats, however, this was significantly attenuated in Lipo-SLex-treated cats (82 ± 7 vs. 28 ± 3 PMNs/mm2, P < 0.01). Myeloperoxidase activity in the ischaemic myocardium, a marker of PMN accumulation, was also significantly attenuated in Lipo-SLex-treated cats compared to liposomes without SLex (P < 0.01). Conclusions. Liposome-conjugated SLex-oligosaccharide attenuates myocardial necrosis and preserves coronary endothelial function following MI/R in vivo. The mechanism appears to be mediated by inhibition of the initial PMN-endothelial interaction and eventual accumulation into the ischaemic cardiac tissue. The liposome-SLex complex may be an efficient drug formulation for acute inflammatory diseases.

KEYWORDS Myocardial ischemia; Reperfusion; Myocardial infarct size; Liposome; Selectins; Neutrophils; Endothelium; Cat heart; Cat coronary artery


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