Department of Cardiology, Xijing Hospital, The Fourth Military Medical University, Xi'an, China.
J Mol Cell Cardiol. 2010 Sep;49(3):354-61. doi: 10.1016/j.yjmcc.2010.05.002. Epub 2010 May 16.
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.
高血糖（HG）显著增加了有和没有既定糖尿病的心肌梗死（MI）患者的死亡率。具体的潜在机制尚不清楚。本研究试图确定硫氧还蛋白-1（Trx-1）的硝化失活是否可能导致高血糖状态下观察到的心肌缺血/再灌注（I/R）损伤加剧。在小鼠中通过多次腹腔内注射低剂量链脲佐菌素（STZ）诱导糖尿病。结扎左前降支冠状动脉 30 分钟后缺血，松开结扣（用于凋亡、Trx-1-活性和-硝化测定）或 24 小时后再灌注（用于心功能和梗死面积测定）。在再灌注前 10 分钟，糖尿病小鼠随机接受载体、EUK134（过氧亚硝酸盐清除剂）、重组人硫氧还蛋白-1（rhTrx-1）或 SIN-1（过氧亚硝酸盐供体）硝化硫氧还蛋白-1（N-Trx-1）给药。糖尿病加剧了 I/R 引起的心肌损伤，表现为糖尿病小鼠的梗死面积进一步扩大、凋亡增加和心功能降低。在 I/R 前，糖尿病心脏中的 Trx-1 硝化失活增加，并且在 I/R 后进一步放大。在再灌注前用 EUK134 或 rhTrx-1 治疗，但不是 N-Trx-1 治疗，可显著降低 Trx-1 硝化，保持 Trx-1 活性，减轻凋亡，减少梗死面积，改善糖尿病小鼠的心功能。综上所述，我们的结果表明，HG 通过增强 Trx-1 的硝化失活增加了心脏对 I/R 损伤的易感性，表明阻断 Trx-1 硝化或补充外源性 rhTrx-1 可能代表治疗糖尿病患者 MI 后心脏损伤的新疗法。
