Cardioprotection by liposome-conjugated sialyl Lewisx-oligosaccharide in myocardial ischaemia and reperfusion injury.
OBJECTIVE
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 micrograms 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 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.
Murohara
T
T
Department of Physiology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Margiotta
J
J
Phillips
L M
LM
Paulson
J C
JC
DeFrees
S
S
Zalipsky
S
S
Guo
L S
LS
Lefer
A M
AM
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D000001:Calcimycin / Q000494:pharmacology; D002415:Cats; D002448:Cell Adhesion / Q000187:drug effects; D003402:Creatine Kinase / Q000097:blood; D004337:Drug Carriers; D004730:Endothelium, Vascular / Q000187:drug effects; D066298:In Vitro Techniques; D008081:Liposomes; D008297:Male; D017202:Myocardial Ischemia / Q000188:drug therapy* / Q000201:enzymology; D015428:Myocardial Reperfusion Injury / Q000201:enzymology / Q000517:prevention & control*; D009206:Myocardium / Q000201:enzymology; D009504:Neutrophils / Q000502:physiology; D009844:Oligosaccharides / Q000008:administration & dosage*; D009195:Peroxidase / Q000378:metabolism; D000080506:Sialyl Lewis X Antigen; D013917:Thrombin / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects
D004337:Drug Carriers; D008081:Liposomes; D009844:Oligosaccharides; D000080506:Sialyl Lewis X Antigen; D000001:Calcimycin; D009195:Peroxidase; D003402:Creatine Kinase; D013917:Thrombin; D000109:Acetylcholine