Dominant negative 14-3-3 promotes cardiomyocyte apoptosis in early stage of type I diabetes mellitus through activation of JNK
Dominant negative 14-3-3 promotes cardiomyocyte apoptosis in early stage of type I diabetes mellitus through activation of JNK
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DOI：
10.1016/j.bbrc.2004.06.023
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发表时间：
2004-07-30
影响因子：
3.1
通讯作者：
Aizawa, Y
中科院分区：
文献类型：
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作者：
Gurusamy, N;Watanabe, K;Aizawa, Y
14-3-3家族成员是二聚体，磷丝氨酸结合蛋白，调节信号转导，凋亡和检查点控制途径。近年来，心肌细胞凋亡在1型糖尿病中被发现。为了研究糖尿病诱导心肌细胞凋亡的分子机制，我们研究了14-3-3蛋白和MAPK通路在心脏特异性表达14-3-3 -3eta （DN-14-3-3）的转基因小鼠中的作用。p38 MAPK在链脲霉素诱导糖尿病后1、28和56天高度激活，而JNK激活在第3天达到峰值，随后下降。相比之下，ERK1/2在糖尿病心肌中未被激活。心肌细胞凋亡在第3天达到高峰，在第7、28和56天减少。与非转基因小鼠相比，DN-14-3-3小鼠的p38 MAPK和JNK活化以及心肌细胞凋亡显著增加。此外，我们发现JNK活化与糖尿病心肌细胞凋亡之间存在显著相关性。这些结果首次表明14-3-3蛋白通过抑制JNK通路在糖尿病心肌中发挥重要的抗凋亡作用。(C) 2004爱思唯尔公司版权所有。
14-3-3 family members are dimeric, phosphoserine binding proteins that regulate signal transduction, apoptotic, and checkpoint control pathways. Recently, cardiomyocyte apoptosis has been characterized in type I diabetes mellitus. In order to study the molecular mechanism underlying diabetes-induced cardiomyocyte apoptosis, we examined the role of 14-3-3 protein and MAPK pathways in transgenic mice with cardiac specific expression of dominant negative 14-3-3eta (DN-14-3-3). p38 MAPK was highly activated 1, 28, and 56 days after diabetes induction by streptozotocin, whereas peak JNK activation was found on day 3 and decreased afterwards. In contrast, ERK1/2 were not activated in diabetic myocardium. Cardiomyocyte apoptosis was peaked on day 3 and decreased on 7, 28, and 56 days. p38 MAPK and JNK activation as well as cardiomyocyte apoptosis were greatly increased in DN-14-3-3 mice relative to non-transgenic mice. Moreover, we found a significant correlation between JNK activation and apoptosis in diabetic myocardium. These results indicate for the first time that 14-3-3 protein plays a critical anti-apoptotic role in diabetic myocardium by inhibiting the JNK pathway. (C) 2004 Elsevier Inc. All rights reserved.