Targeted antioxidant treatment decreases cardiac alternans associated with chronic myocardial infarction.
Targeted antioxidant treatment decreases cardiac alternans associated with chronic myocardial infarction.
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DOI：
10.1161/circep.114.001789
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发表时间：
2015-02
期刊：
影响因子：
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通讯作者：
Laurita KR
中科院分区：
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作者：
Plummer BN;Liu H;Wan X;Deschênes I;Laurita KR
在心肌梗塞 (MI) 中，复极交替是一种有效的心律失常底物，与位于肌浆网 (SR) 中的 Ca2+ 循环蛋白（例如 SERCA2a）有关。 MI 还与氧化应激和黄嘌呤氧化酶 (XO) 活性增加有关，黄嘌呤氧化酶 (XO) 活性是 SR 中活性氧 (ROS) 的重要来源，可能会降低 SERCA2a 功能。我们假设在慢性 MI 中，XO 介导的 SERCA2a 氧化是心脏交替的机制。雄性Lewis大鼠接受LAD结扎（n=54）或假手术（n=24）。 4 周时，进行细胞内 Ca2+ 和 ROS 的光学绘图。 XO抑制剂别嘌呤醇（ALLO，50μmol/L）前后快速起搏（300-120ms）诱导心电图T波交替（ECG ALT）和Ca2+瞬时交替（Ca2+ALT）。在 MI 中，心电图 ALT (2.32±0.41%) 和 Ca2+ ALT (22.3±4.5%) 显着高于假手术组 (0.18±0.08%，p<0.001；0.79±0.32%，p<0.01)。此外，与假手术相比，MI 中 ROS 增加了 137%（p<0.01），SERCA2a 氧化增加了 30%（p<0.05）。 ALLO治疗显着降低了ECG ALT（-77±9%，p<0.05）和Ca2+ ALT（-56±7%，p<0.05），重要的是，减少了ROS（-65%，p<0.01）和SERCA2a的氧化（-38%，p<0.05）。 CaMKII 抑制和一般抗氧化治疗对 ECG ALT 和 Ca2+ ALT 没有影响。这些结果首次证明，在 MI 中，XO 中 ROS 的增加是复极交替的重要原因。这表明针对 XO ROS 产生可能有效预防慢性 MI 中的心律失常基质。
In myocardial infarction (MI), repolarization alternans is a potent arrhythmia substrate that has been linked to Ca2+ cycling proteins, such as SERCA2a, located in the sarcoplasmic reticulum (SR). MI is also associated with oxidative stress and increased xanthine oxidase (XO) activity, an important source of reactive oxygen species (ROS) in the SR that may reduce SERCA2a function. We hypothesize that in chronic MI, XO mediated oxidation of SERCA2a is a mechanism of cardiac alternans. Male Lewis rats underwent ligation of the LAD (n=54) or sham procedure (n=24). At 4 weeks, optical mapping of intracellular Ca2+ and ROS were performed. ECG T-wave alternans (ECG ALT) and Ca2+ transient alternans (Ca2+ALT) were induced by rapid pacing (300–120ms) before and after the XO inhibitor allopurinol (ALLO, 50μmol/L). In MI, ECG ALT (2.32±0.41%) and Ca2+ ALT (22.3±4.5%) were significantly greater compared to sham (0.18±0.08%, p<0.001; 0.79±0.32%, p<0.01). Additionally, ROS was increased by 137% (p<0.01) and oxidation of SERCA2a by 30% (p<0.05) in MI compared to sham. Treatment with ALLO significantly decreased ECG ALT (−77±9%, p<0.05) and Ca2+ ALT (−56±7%, p<0.05) and, importantly, reduced ROS (−65%, p<0.01) and oxidation of SERCA2a (−38%, p<0.05). CaMKII inhibition and general antioxidant treatment had no effect on ECG ALT and Ca2+ ALT. These results demonstrate, for the first time, that in MI increased ROS from XO is a significant cause of repolarization alternans. This suggests that targeting XO ROS production may be effective at preventing arrhythmia substrates in chronic MI.