Abstract 11916: The Vicious Crosstalk Between Rage and Thioredoxin Nitrative Inactivation in the Diabetic Myocardial Ischemia/Reperfusion
The receptor for advanced glycation end products (RAGE) and thioredoxin (Trx) play opposing role in diabetic myocardial ischemia/reperfusion (MI/R) injury. RAGE has been reported to promote oxidative/nitrative stress and we have recently demonstrated that nitrative modification causes Trx inactivation. However, the relation between increased RAGE expression and reduced Trx activity in the diabetic heart in concerning to their role in increased MI/R injury in diabetic heart has not been previously investigated. Diabetes was introduced by multiple intraperitoneal injections of low-dose streptozotocin (STZ), and cardiac RAGE expression was inhibited (<18% of control) by intramyocardial siRNA injection. Compared with non-diabetic heart, diabetic heart had increased RAGE expression and CML content, reduced Trx-1 activity, increased Trx nitration, larger infarct size and poorer cardiac function (all P<0.01) after MI/R. Administration of sRAGE or RAGE knockdown in diabetic mice decreased MI/R-induced nitrotyrosine content, reduced Trx nitration, preserved Trx activity (all P<0.01 vs. vehicle), and decreased infarct size (P<0.05). Conversely, administration of EUK134 (a peroxynitrite scavenger) or reduced hTrx, but not nitratively modified hTrx, attenuated MI/R-induced RAGE expression and CML content (all P<0.01 vs. vehicle), and improved cardiac function (P<0.05) in diabetic mice. Pre-exposing cardiomyocytes to AGE increased Trx nitration, reduced Trx activity, and increased simulated I/R injury (all P<0.05). All these effects were blocked by treatment with sRAGE or RAGE knockdown. Conversely, treatment of AGE pre-treated cardiomyocytes with EUK134 and hTrx, but not nitrated hTrx, attenuated the simulated I/R-induced RAGE expression (P<0.05). Collectively, we demonstrate that AGE caused Trx nitrative inactivation in a RAGE-dependent fashion. Conversely, nitrative modification of Trx blocked its inhibitory effects on RAGE overexpression in the diabetic heart. This is the first direct evidence that there exists a vicious crosstalk between RAGE overexpression and nitrative Trx inactivation, suggesting that interventions blocking this vicious crosstalk may be novel therapy that can mitigate MI/R injury in diabetic patients.
- Type 2 Diabetes
- Cell signaling
- Free radicals/Free-radical scavengers
- Ischemia reperfusion
- © 2011 by American Heart Association, Inc.