Abstract 14930: A Glyburide Analogue Free of the Cyclohexylurea Moiety Inhibits the Inflammasome in the Heart During Acute Myocardial Infarction
Background: The formation of the cryopyrin inflammasome in the heart during AMI amplifies the inflammatory response and mediates further damage. Glyburide has cryopyrin-inhibitory activity in vitro, but the use of glyburide as a cryopyrin inhibitor in vivo would require very high doses beyond those used in diabetes, associated with lethal hypoglycemia. The aim of this study was to measure the effects of a glyburide analogue, free of the cyclohexylurea moiety involved in insulin release, on the cryopyrin inflammasome.
Methods and Results: We synthetized a glyburide analogue (GA) that displayed no effect on glucose metabolism. HL-1 cardiomyocytes were treated with LPS (25 ng/ml) for 2 hours followed by ATP (5 mM) for 1 hour to induce the formation of the cryopyrin inflammasome measured as increased caspase-1 activity and cell death. These effects were prevented by GA (Figure). GA was well tolerated and it had no effects on the glucose levels in the mouse in vivo (Figure). Zymosan A (30mg/Kg) induces peritonitis mediated by the cryopyrin inflammasome, and pre-treatment with GA (5, 20 and 100 mg/kg) limited the degree of leukocyte infiltration in the peritoneal cavity in a dose-dependent manner (all p<0.05). Finally, treatment with GA (100 mg/kg) significantly inhibited the inflammasome (caspase-1 activity) in the heart and reduced infarct size in a model of ischemia (30 min) and reperfusion (24 hours) in the mouse (Figure).
Conclusions: A newly designed glyburide analog (GA) inhibits the formation of the cryopyrin inflammasome in cardiomyocytes and limits the infarct size following myocardial ischemia/reperfusion in the mouse, without affecting glucose metabolism.
- © 2013 by American Heart Association, Inc.