Activation of Na+/K+-ATPase attenuates high glucose-induced H9c2 cell apoptosis via suppressing ROS accumulation and MAPKs activities by DRm217.
Activation of Na+/K+-ATPase attenuates high glucose-induced H9c2 cell apoptosis via suppressing ROS accumulation and MAPKs activities by DRm217.
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DOI：
10.1093/abbs/gmw079
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发表时间：
2016-10
影响因子：
3.7
通讯作者：
Xiaofei Yan;Meng Xun;Jing Li;Litao Wu;Xiaojuan Dou;Jin Zheng
中科院分区：
文献类型：
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作者：
Xiaofei Yan;Meng Xun;Jing Li;Litao Wu;Xiaojuan Dou;Jin Zheng
高血压是糖尿病心肌细胞凋亡和功能障碍的主要原因之一。大量研究表明，Na+/K+-ATP酶活性降低与糖尿病心肌病的发生密切相关。然而，直接激活的Na+/K+-ATP酶在高糖诱导的心肌损伤中的作用尚不清楚。我们发现DRm 217是Na+/K+-ATP酶DR区的特异性单克隆抗体和直接激活剂，它可以防止高糖诱导的H9 c2细胞损伤、活性氧（ROS）释放和线粒体功能障碍。高糖处理降低Na+/K+-ATP酶活性，增加细胞内Ca ~（2+）水平，而DRm 217则增加Na+/K+-ATP酶活性，减轻Ca ~（2+）超载。抑制Ca ~（2+）超载或关闭钠钙交换器（NCX通道）可逆转高糖诱导的ROS增加和细胞损伤。此外，DRm 217还能显著抑制高糖诱导的p38、JNK和ERK 1/2磷酸化，这些磷酸化参与了高糖诱导的细胞损伤和ROS的积累。我们的研究结果表明，DRm 217可以保护心脏免受高糖的有害影响。通过特异性Na+/K+-ATP酶激活剂预防高糖诱导的心肌细胞损伤可能是一种有吸引力的治疗选择。
Hyperglycemia is one of the major factors responsible for the myocardial apoptosis and dysfunction in diabetes. Many studies have proved that there is a close relationship between decreased Na+/K+-ATPase activity and diabetic cardiomyopathy. However, the effect of directly activated Na+/K+-ATPase on high glucose-induced myocardial injury is still unknown. Here we found that DRm217, a Na+/K+-ATPase's DR-region specific monoclonal antibody and direct activator, could prevent high glucose-induced H9c2 cell injury, reactive oxygen species (ROS) release, and mitochondrial dysfunction. High glucose-treatment decreased Na+/K+-ATPase activity and increased intracellular Ca2+ level, whereas DRm217 increased Na+/K+-ATPase activity and alleviated Ca2+ overload. Inhibition of Ca2+ overload or closing sodium calcium exchanger (NCX channel) could reverse high glucose-induced ROS increasing and cell injury. In addition, DRm217 could significantly attenuate high glucose-induced p38, JNK and ERK1/2 phosphorylation, which were involved in high glucose-induced cell injury and ROS accumulation. Our findings suggest that DRm217 may protect against the deleterious effects of high glucose in the heart. Prevention of high glucose-induced myocardial cell injury by specific Na+/K+-ATPase activator may be an attractive therapeutic option.