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首页> 美国卫生研究院文献>other >ß-Blocker Timolol Prevents Arrhythmogenic Ca2+ Release and Normalizes Ca2+ and Zn2+ Dyshomeostasis in Hyperglycemic Rat Heart
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ß-Blocker Timolol Prevents Arrhythmogenic Ca2+ Release and Normalizes Ca2+ and Zn2+ Dyshomeostasis in Hyperglycemic Rat Heart

机译：ß-阻滞剂Timolol预防高血糖大鼠心脏的致心律失常性Ca2 +释放并正常化Ca2 +和Zn2 +血透异常

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Defective cardiac mechanical activity in diabetes results from alterations in intracellular Ca2+ handling, in part, due to increased oxidative stress. Beta-blockers demonstrate marked beneficial effects in heart dysfunction with scavenging free radicals and/or acting as an antioxidant. The aim of this study was to address how β-blocker timolol-treatment of diabetic rats exerts cardioprotection. Timolol-treatment (12-week), one-week following diabetes induction, prevented diabetes-induced depressed left ventricular basal contractile activity, prolonged cellular electrical activity, and attenuated the increase in isolated-cardiomyocyte size without hyperglycemic effect. Both in vivo and in vitro timolol-treatment of diabetic cardiomyocytes prevented the altered kinetic parameters of Ca2+ transients and reduced Ca2+ loading of sarcoplasmic reticulum (SR), basal intracellular free Ca2+ and Zn2+ ([Ca2+]i and [Zn2+]i), and spatio-temporal properties of the Ca2+ sparks, significantly. Timolol also antagonized hyperphosphorylation of cardiac ryanodine receptor (RyR2), and significantly restored depleted protein levels of both RyR2 and calstabin2. Western blot analysis demonstrated that timolol-treatment also significantly normalized depressed levels of some [Ca2+]i-handling regulators, such as Na+/Ca2+ exchanger (NCX) and phospho-phospholamban (pPLN) to PLN ratio. Incubation of diabetic cardiomyocytes with 4-mM glutathione exerted similar beneficial effects on RyR2-macromolecular complex and basal levels of both [Ca2+]i and [Zn2+]i, increased intracellular Zn2+ hyperphosphorylated RyR2 in a concentration-dependent manner. Timolol also led to a balanced oxidant/antioxidant level in both heart and circulation and prevented altered cellular redox state of the heart. We thus report, for the first time, that the preventing effect of timolol, directly targeting heart, seems to be associated with a normalization of macromolecular complex of RyR2 and some Ca2+ handling regulators, and prevention of Ca2+ leak, and thereby normalization of both [Ca2+]i and [Zn2+]i homeostasis in diabetic rat heart, at least in part by controlling the cellular redox status of hyperglycemic cardiomyocytes.
机译：糖尿病患者心脏机械活动不良是由于细胞内Ca 2 + 处理方式的改变，部分原因是氧化应激增加。 β受体阻滞剂通过清除自由基和/或充当抗氧化剂，对心脏功能障碍显示出明显的有益作用。这项研究的目的是解决糖尿病大鼠β-阻滞剂噻吗洛尔的治疗如何发挥心脏保护作用。糖尿病诱导后第一个星期的蒂莫洛尔治疗（12周）可预防糖尿病引起的左心室基础收缩活性降低，细胞电活动延长，并减轻孤立的心肌细胞大小的增加，而无高血糖作用。体内和体外替莫洛尔治疗糖尿病心肌细胞均能防止Ca 2 + 瞬变动力学参数的改变，并减少基础肌浆网（SR）的Ca 2 + 负荷细胞内游离Ca 2 + 和Zn 2 + （[Ca 2 + ] i和[Zn 2 + ] i i）和Ca 2 + 火花的时空特性。替莫洛尔还拮抗心脏ryanodine受体（RyR2）的过度磷酸化，并显着恢复RyR2和calstabin2的蛋白质消耗水平。 Western印迹分析表明，噻吗洛尔处理还可以显着标准化某些[Ca 2 + ] i处理调节剂的抑郁水平，例如Na + / Ca 2+ 交换器（NCX）和磷化磷脂（pPLN）与PLN的比率。用4-mM谷胱甘肽孵育糖尿病心肌细胞对RyR2-大分子复合物和[Ca 2 + ] i和[Zn 2 + ] i的基础水平具有相似的有益作用。 ，以浓度依赖的方式增加细胞内Zn 2 + 超磷酸化的RyR2。替莫洛尔还可以在心脏和血液循环中达到平衡的氧化剂/抗氧化剂水平，并防止心脏细胞氧化还原状态的改变。因此，我们首次报道了直接针对心脏的噻吗洛尔的预防作用似乎与RyR2和一些Ca 2 + 处理调节剂的大分子复合物的正常化以及预防Ca 2 + 泄漏，从而使糖尿病大鼠心脏中[Ca 2 + ] i和[Zn 2 + ] i体内稳态均正常化，至少部分地通过控制高血糖心肌细胞的细胞氧化还原状态。

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