Nitrative inactivation of thioredoxin-1 increases vulnerability of diabetic hearts to ischemia/reperfusion injury.

Abstract

Hyperglycemia (HG) significantly increases mortality after myocardial infarction (MI) in patients with and without established diabetes. The specific underlying mechanism remains unknown. The present study attempted to determine whether nitrative inactivation of thioredoxin-1 (Trx-1) may contribute to the exaggerated myocardial ischemia/reperfusion (I/R) injury observed in the hyperglycemic condition. Diabetes was induced by multiple intraperitoneal injections of low-dose streptozotocin (STZ) in mice. After 30 min ischemia by slip-knot ligature of the left anterior descending coronary artery, the myocardium was reperfused for 3h after knot release (for apoptosis, Trx-1-activity, and -nitration determination) or 24h (for cardiac function and infarct size determination). At 10 min before reperfusion, diabetic mice were randomized to receive vehicle, EUK134 (a peroxynitrite scavenger), recombinant human Trx-1 (rhTrx-1), or SIN-1 (a peroxynitrite donor) nitrated Trx-1 (N-Trx-1) administration. Diabetes intensified I/R-induced myocardial injury, evidenced by further enlarged infarct size, increased apoptosis, and decreased cardiac function in diabetic mice. Trx-1 nitrative inactivation was elevated in the diabetic heart before I/R and was further amplified after I/R. Treatment with EUK134 or rhTrx-1, but not N-Trx-1, before reperfusion significantly reduced Trx-1 nitration, preserved Trx-1 activity, attenuated apoptosis, reduced infarct size, and improved cardiac function in diabetic mice. Taken together, our results demonstrated that HG increased cardiac vulnerability to I/R injury by enhancing nitrative inactivation of Trx-1, suggesting that blockade of Trx-1 nitration, or supplementation of exogenous rhTrx-1, might represent novel therapies to attenuate cardiac injury after MI in diabetic patients.

• Authors: Tao Yin, Rongrong Hou, Shaowei Liu, Wayne Bond Lau, Haichang Wang, Ling Tao
• Journal: Journal of molecular and cellular cardiology (J Mol Cell Cardiol) Vol. 49 Issue 3 Pg. 354-61 (Sep 2010) ISSN: 1095-8584 [Electronic] England
• PMID: 20497906 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 2010 Elsevier Ltd. All rights reserved.

Chemical References

• Blood Glucose
• Nitrates
• Txn1 protein, mouse
• Peroxynitrous Acid
• 3-nitrotyrosine
• Tyrosine
• Thioredoxins
• p38 Mitogen-Activated Protein Kinases

Topics

• Animals
• Apoptosis
• Blood Glucose (metabolism)
• Cells, Cultured
• Diabetes Mellitus, Experimental (metabolism)
• Diabetic Cardiomyopathies (metabolism, pathology)
• Heart (physiology)
• Hyperglycemia (metabolism)
• Immunoblotting
• Immunoprecipitation
• Mice
• Myocardial Reperfusion Injury (metabolism, pathology)
• Nitrates (metabolism)
• Nitrosation
• Peroxynitrous Acid (metabolism)
• Thioredoxins (metabolism)
• Tyrosine (analogs & derivatives, metabolism)
• p38 Mitogen-Activated Protein Kinases (metabolism)