Nitrative inactivation of thioredoxin-1 increases vulnerability of diabetic hearts to ischemia/reperfusion injury.
Publication/Presentation Date
9-1-2010
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.
Volume
49
Issue
3
First Page
354
Last Page
361
ISSN
1095-8584
Published In/Presented At
Yin, T., Hou, R., Liu, S., Lau, W. B., Wang, H., & Tao, L. (2010). Nitrative inactivation of thioredoxin-1 increases vulnerability of diabetic hearts to ischemia/reperfusion injury. Journal of molecular and cellular cardiology, 49(3), 354–361. https://doi.org/10.1016/j.yjmcc.2010.05.002
Disciplines
Business Administration, Management, and Operations | Health and Medical Administration | Management Sciences and Quantitative Methods
PubMedID
20497906
Department(s)
Administration and Leadership
Document Type
Article