Cardioprotective mechanisms of mitochondria-targeted S-nitrosating agent and adenosine triphosphate-sensitive potassium channel opener are mutually exclusive.
Cardioprotective mechanisms of mitochondria-targeted S-nitrosating agent and adenosine triphosphate-sensitive potassium channel opener are mutually exclusive.
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DOI：
10.1016/j.xjon.2021.07.036
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发表时间：
2021-12
期刊：
影响因子：
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通讯作者：
Lawton, Jennifer S
中科院分区：
文献类型：
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作者：
Ahmad, Thaniyyah;Wang, Jie;Velez, Ana Karen;Suarez-Pierre, Alejandro;Clement, Kathleen C;Dong, Jie;Sebestyen, Krisztian;Canner, Joseph K;Murphy, Michael P;Lawton, Jennifer S
暴露在应激状态下的肌细胞表现出显著的肿胀和收缩能力降低。三磷酸腺苷敏感钾(KATP)通道开放剂二氮嗪(DZX)通过一种未知的机制改善这些后果。KATP通道开放剂还在多种动物模型中提供心脏保护。一氧化氮供体同样具有心脏保护作用，它们与KATP激活的结合可能提供协同益处。我们假设线粒体靶向的S亚硝酸盐(MitoSnO)与DZX具有协同的心脏保护作用。比较应激结束时Tyrode生理溶液(20分钟)和应激(高钾停搏液[CPG])和应激(n=20~20；n=20；20分钟)加或不加MitoSNO(n=20~11)后心肌细胞体积和收缩能力的变化。小鼠离体心在全脑缺血(90分钟)前给予CpG+DZX(n=8~10)，在缺血结束时加或不加MitoSNO(n=8)，然后再灌流(30分钟)。使用线性混合模型比较左心室(LV)压力，以评估治疗对结果的影响，并调整基线和球囊容量。应激(CPG)与DZX和MitoSNO单独预防的心肌细胞收缩能力降低有关；然而，它们的联合作用与心脏保护的丧失有关。类似地，DZX和MitoSNO改善了长时间缺血后的左心功能，与单独使用CPG相比，它们的联合应用失去了心脏保护作用。MitoSNO和DZX提供了因联合使用而失去的心脏保护作用，这表明它们的作用机制是相互排斥的。缺乏协同的有益效果使人们对DZX的心脏保护机制有了更多的了解，并将有助于规划未来的临床试验。
Myocytes exposed to stress exhibit significant swelling and reduced contractility. These consequences are ameliorated by adenosine triphosphate–sensitive potassium (KATP) channel opener diazoxide (DZX) via an unknown mechanism. KATP channel openers also provide cardioprotection in multiple animal models. Nitric oxide donors are similarly cardioprotective, and their combination with KATP activation may provide synergistic benefit. We hypothesized that mitochondria-targeted S-nitrosating agent (MitoSNO) would provide synergistic cardioprotection with DZX. Myocyte volume and contractility were compared following Tyrode's physiologic solution (20 minutes) and stress (hyperkalemic cardioplegia [CPG] ± DZX; n = 5-20 each; 20 minutes) with or without MitoSNO (n = 5-11 each) at the end of stress, followed by Tyrode's solution (20 minutes). Isolated mouse hearts received CPG ± DZX (n = 8-10 each) before global ischemia (90 minutes) with or without MitoSNO (n = 8 each) at the end of ischemia, followed by reperfusion (30 minutes). Left ventricular (LV) pressures were compared using a linear mixed model to assess the impact of treatment on the outcome, adjusting for baseline and balloon volume. Stress (CPG) was associated with reduced myocyte contractility that was prevented by DZX and MitoSNO individually; however, their combination was associated with loss of cardioprotection. Similarly, DZX and MitoSNO improved LV function after prolonged ischemia compared with CPG alone, and cardioprotection was lost with their combination. MitoSNO and DZX provide cardioprotection that is lost with their combination, suggesting mutually exclusive mechanisms of action. The lack of a synergistic beneficial effect informs the current knowledge of the cardioprotective mechanisms of DZX and will aid planning of future clinical trials.