Activated protein C prevents methylglyoxal-induced endoplasmic reticulum stress and cardiomyocyte apoptosis via regulation of the AMP-activated protein kinase signaling pathway
Activated protein C prevents methylglyoxal-induced endoplasmic reticulum stress and cardiomyocyte apoptosis via regulation of the AMP-activated protein kinase signaling pathway
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DOI：
10.1016/j.bbrc.2016.10.106
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发表时间：
2016-11-25
影响因子：
3.1
通讯作者：
Woo, Chang-Hoon
中科院分区：
文献类型：
--
作者：
Nam, Dae-Hwan;Han, Jung-Hwa;Woo, Chang-Hoon
以往的流行病学研究表明，甲基乙二醛（MGO）水平在糖尿病心血管疾病中受到高度调节。我们以前也报道过MGO介导心肌细胞的内质网应激和凋亡。此外，活化蛋白C（APC）最近已被证明对ER应激起保护作用，以及通过增强AMP活化蛋白激酶（AMPK）信号通路对缺血和再灌注损伤起心脏保护作用。因此，我们假设APC通过抑制ER应激来保护MGO诱导的心肌细胞凋亡。我们的结果表明，APC抑制MGO诱导的心肌细胞凋亡和ER应激相关基因的表达。此外，APC抑制MGO诱导的Ca 2+动员和活性氧的产生。与此相反，AMPK信号抑制剂取消APC的细胞保护作用。总的来说，这些数据描绘了AMPK信号转导在抑制ER应激反应通过激活APC在MGO诱导的心肌细胞凋亡的关键作用。因此，APC可能是糖尿病心血管并发症如糖尿病心肌病的一个潜在的新的治疗靶点。(C)2016 Elsevier Inc. All rights reserved.
Previous epidemiological studies have shown that methylglyoxal (MGO) levels are highly regulated in diabetic cardiovascular diseases. We have also previously reported that MGO mediates ER stress and apoptosis in cardiomyocytes. Furthermore, activated protein C (APC) has recently been shown to play a protective role against ER stress, as well as a cardioprotective role against ischemia and reperfusion injury by augmenting the AMP-activated protein kinase (AMPK) signaling pathway. Therefore, we hypothesized that APC protects against MGO-induced cardiomyocyte apoptosis through the inhibition of ER stress. Our results showed that APC inhibited MGO-induced cardiomyocyte apoptosis and ER stress related gene expression. Additionally, APC inhibited MGO-induced Ca2+ mobilization and the generation of reactive oxygen species. In contrast, inhibitors of AMPK signaling abolished the cytoprotective effects of APC. Collectively, these data depict a pivotal role for AMPK signaling in inhibiting ER stress responses via the activation of APC during MGO-induced cardiomyocyte apoptosis. Thus, APC may be a potential novel therapeutic target for the management of diabetic cardiovascular complications such as diabetic cardiomyopathy. (C) 2016 Elsevier Inc. All rights reserved.