Beta-blocker timolol alleviates hyperglycemia-induced cardiac damage via inhibition of endoplasmic reticulum stress
Beta-blocker timolol alleviates hyperglycemia-induced cardiac damage via inhibition of endoplasmic reticulum stress
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DOI：
10.1007/s10863-014-9568-6
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发表时间：
2014-10-01
影响因子：
3
通讯作者：
Turan, Belma
中科院分区：
文献类型：
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作者：
Cicek, Figen Amber;Toy, Aysegul;Turan, Belma
目前的数据支持内质网应激（ERS）的药理学调节剂对糖尿病个体具有治疗潜力。因此，我们的目的是检查噻吗洛尔，具有自由基清除剂的作用，除了作为一种β-受体阻滞剂，是否发挥心脏保护作用，通过抑制ERS反应在糖尿病大鼠与抗氧化剂N-乙酰半胱氨酸（NAC）的比较。组织学数据表明，无论是噻吗洛尔-或NAC-治疗糖尿病大鼠防止心肌组织的线粒体和细胞核的变化，而他们提高心脏细胞的氧化还原状态以及。在这些组中，发现接受噻吗洛尔或NAC治疗的糖尿病大鼠心脏中ER靶向细胞保护性伴侣蛋白GRP 78和钙连接蛋白、未折叠蛋白反应信号传导蛋白CHO/Gadd 153的水平以及钙蛋白酶、BCL-2、磷酸化Akt、p53 A和PML的水平相似，尽管与对照组相比，所有这些参数在未治疗的糖尿病患者中显著保留。考虑到抗凋亡和促凋亡蛋白之间的平衡比例对于维持线粒体/ER功能的重要性，我们的研究结果表明，糖尿病大鼠心脏的ERS是由氧化损伤增加介导的，这反过来又引发了心功能障碍。此外，我们还证明，噻吗洛尔治疗糖尿病大鼠，类似于NAC治疗，诱导良好控制的氧化还原状态和心肌细胞凋亡。因此，我们首次报道噻吗洛尔的心脏保护作用似乎与ER功能的正常化有关，这是由于其在心肌细胞中的抗氧化作用，即使在高血糖下也是如此。
Current data support that pharmacological modulators of endoplasmic reticulum stress (ERS) have therapeutic potential for diabetic individuals. Therefore, we aimed to examine whether timolol, having free radical-scavenger action, besides being a beta-blocker, exerts a cardioprotective effect via inhibition of ERS response in diabetic rats in a comparison with an antioxidant N-acetylcysteine (NAC). Histopathological data showed that either timolol- or NAC-treatment of diabetic rats prevented the changes in mitochondria and nucleus of the cardiac tissue while they enhanced the cellular redox-state in heart as well. The levels of ER-targeted cytoprotective chaperones GRP78 and calnexin, unfolded protein response signaling protein CHO/Gadd153 besides the levels of calpain, BCL-2, phospho-Akt, PUMA, and PML in the hearts from diabetic rats, treated with either timolol or NAC, are found to be similar among these groups, although all these parameters were markedly preserved in the untreated diabetics compared to those of the controls. Taken into consideration how important a balanced-ratio between anti-apoptotic and pro-apoptotic proteins for the maintenance mitochondria/ER function, our results suggest that ERS in diabetic rat heart is mediated by increased oxidative damage, which in turn triggers cardiac dysfunction. Moreover, we also demonstrated that timolol treatment of diabetic rats, similar to NAC treatment, induced a well-controlled redox-state and apoptosis in cardiac myocardium. We, thus for the first time, report that cardioprotective effect of timolol seems to be associated with normalization of ER function due to its antioxidant action in cardiomyocytes even under hyperglycemia.