Glutathione oxidation unmasks proarrhythmic vulnerability of chronically hyperglycemic guinea pigs.
Glutathione oxidation unmasks proarrhythmic vulnerability of chronically hyperglycemic guinea pigs.
复制标题
谷胱甘肽氧化揭示了长期高血糖豚鼠的致心律失常脆弱性。
DOI：
10.1152/ajpheart.00026.2012
复制
发表时间：
2013
期刊：
影响因子：
--
通讯作者：
Akar,FadiG
中科院分区：
文献类型：
--
作者：
Xie,Chaoqin;Biary,Nora;Tocchetti,CarloG;Aon,MiguelA;Paolocci,Nazareno;Kauffman,Justin;Akar,FadiG
1型糖尿病患者的慢性高血糖与氧化应激（OS）和猝死有关。机制联系尚不清楚。我们研究了在慢性高血糖模型中，通过GSH氧化用OS激发之前和之后的电生理（EP）特性的变化，并测试了胰岛素对EP重构的可逆性。豚鼠在注射链脲佐菌素（STZ）或生理盐水（假）后存活1个月。治疗组每日给予胰岛素治疗2周，以逆转STZ诱导的高血糖（STZ + Ins）。使用高分辨率光学动作电位标测在用二酰胺激发心脏之前和之后测量EP特性。尽管与假手术（P= 0.004）和STZ +胰岛素（P= 0.002）动物相比，STZ中的葡萄糖水平升高，但基线时平均动作电位时程（APD）和心律失常倾向未改变。与假手术心脏相比，联胺促进了早期（<10 min）的心律失常触发形成，反映在STZ（P= 0.045）和STZ + Ins（P= 0.033）心脏中的心律失常评分指数较高。与假手术心脏相比，STZ和STZ + Ins心脏对二酰胺的反应APD异质性更明显增加。在30 min内，联胺分别导致3/6、2/5、1/5和0/4 STZ、STZ + Ins、假手术和正常心脏自发发生室性心动过速和室颤（VT/VF）。与无VT/VF的心脏相比，易发生VT/VF的心脏表现出更大的APD异质性（P= 0.010）。最后，STZ中EP性质的改变不能被胰岛素挽救。总之，在慢性高血糖豚鼠模型中，GSH氧化增强了APD异质性并增加了心律失常评分指数。尽管胰岛素使血糖水平正常化，但这些促血糖特性并不逆转，这表明靶向抗氧化防御对心律失常抑制的重要性。
Chronic hyperglycemia in type-1 diabetes mellitus is associated with oxidative stress (OS) and sudden death. Mechanistic links remain unclear. We investigated changes in electrophysiological (EP) properties in a model of chronic hyperglycemia before and after challenge with OS by GSH oxidation and tested reversibility of EP remodeling by insulin. Guinea pigs survived for 1 mo following streptozotocin (STZ) or saline (sham) injection. A treatment group received daily insulin for 2 wk to reverse STZ-induced hyperglycemia (STZ + Ins). EP properties were measured using high-resolution optical action potential mapping before and after challenge of hearts with diamide. Despite elevation of glucose levels in STZ compared with sham-operated (P= 0.004) and STZ + Ins (P= 0.002) animals, average action potential duration (APD) and arrhythmia propensity were not altered at baseline. Diamide promoted early (<10 min) formation of arrhythmic triggers reflected by a higher arrhythmia scoring index in STZ (P= 0.045) and STZ + Ins (P= 0.033) hearts compared with sham-operated hearts. APD heterogeneity underwent a more pronounced increase in response to diamide in STZ and STZ + Ins hearts compared with sham-operated hearts. Within 30 min, diamide resulted in spontaneous incidence of ventricular tachycardia and ventricular fibrillation (VT/VF) in 3/6, 2/5, 1/5, and 0/4 STZ, STZ + Ins, sham-operated, and normal hearts, respectively. Hearts prone to VT/VF exhibited greater APD heterogeneity (P= 0.010) compared with their VT/VF-free counterparts. Finally, altered EP properties in STZ were not rescued by insulin. In conclusion, GSH oxidation enhances APD heterogeneity and increases arrhythmia scoring index in a guinea pig model of chronic hyperglycemia. Despite normalization of glycemic levels by insulin, these proarrhythmic properties are not reversed, suggesting the importance of targeting antioxidant defenses for arrhythmia suppression.