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Reduction of myocardial infarct size in vivo by carbohydrate-based glycomimetics
K S Kilgore1, E J Tanhehco, J L Park
1Department of Pharmacology, University of Michigan Medical School, Ann Arbor, USA.
Insights
Natural compounds glycyrrhizin and GM3290 reduce heart damage after ischemia and reperfusion. These glycomimetics, containing carbohydrate moieties, significantly decrease myocardial infarct size by blocking neutrophil adhesion.
Area of Science:
- Cardiology
- Biochemistry
- Pharmacology
Background:
- Myocardial reperfusion injury involves neutrophil adhesion mediated by selectin molecules.
- Blocking selectin interactions with carbohydrate analogs reduces neutrophil influx and infarct size.
Purpose of the Study:
- To evaluate glycyrrhizin (GM1292) and related compounds (GM3290, GM1658) for reducing myocardial infarct size after ischemia/reperfusion.
- To determine structural requirements for cardioprotective activity of these glycomimetics.
Main Methods:
- Anesthetized rabbits underwent 30 min coronary artery occlusion followed by 5 hr reperfusion.
- Glycomimetics were administered intravenously before and during reperfusion.
- Myocardial infarct size was measured and compared between treatment groups.
Main Results:
- GM1292 (two glucuronic acid residues) and GM3290 (one glucuronic acid residue) significantly reduced infarct size compared to vehicle control (P < .05).
- GM1658 (lacking glucuronic acid) showed no protective effect.
- Compounds with carbohydrate moieties demonstrated cardioprotective efficacy.
Conclusions:
- Glycyrrhizin (GM1292) and GM3290 are effective in reducing myocardial injury following ischemia/reperfusion.
- The presence of glucuronic acid residues is crucial for the cardioprotective activity of these glycomimetics.
Abstract:
One of the foremost mechanisms involved in the pathogenesis of myocardial reperfusion injury is the adhesion of neutrophils within the myocardium. The initial neutrophil-endothelial cell interactions are mediated by the selectin family of adhesion molecules. Blockade of this group of adhesion molecules, through the use of synthetic carbohydrate analogs to the selectin ligand sialyl Lewisx and glycomimetics, has been beneficial in reducing neutrophil influx and infarct size. In the present study, glycyrrhizin (GM1292), a natural structural glycomimetic, was analyzed for the ability to decrease myocardial infarct size after regional myocardial ischemia/reperfusion. To determine the structural requirements for optimal cardioprotective activity, two additional compounds related to glycyrrhizin, GM3290 and GM1658 (glycyrrhetinic acid), were studied. The molecular structures of the latter two compounds differ in the number of glucuronic acid residues in their respective molecules. Open-chest, anesthetized rabbits were subjected to 30 min occlusion of the left coronary artery followed by 5 hr of reperfusion. Vehicle or glycomimetic (10 mg/kg/hr) was administered intravenously immediately before the onset of reperfusion and every hour during the reperfusion period. Myocardial infarct size in rabbits treated with GM1292 (two glucuronic acid residues) and GM3290 (one glucuronic acid residue) was reduced significantly when compared with vehicle-treated animals (P < .05). GM1658, which lacks glucuronic acid residues, did not provide a protective effect in vivo. The data suggest that GM1292 and GM3290, which contain carbohydrate moieties, are effective in reducing the degree of myocardial injury after an acute period of ischemia/reperfusion.