PDF(Pubmed)
Abstract：
Activation of the transcription factor NF-κB in cardiomyocytes has been implicated in the development of cardiac function deficits caused by diabetes. NF-κB controls the expression of an array of pro-inflammatory cytokines and chemokines. We recently discovered that the stress response protein regulated in development and DNA damage response 1 (REDD1) was required for increased pro-inflammatory cytokine expression in the hearts of diabetic mice. The studies herein were designed to extend the prior report by investigating the role of REDD1 in NF-κB signaling in cardiomyocytes. REDD1 genetic deletion suppressed NF-κB signaling and nuclear localization of the transcription factor in human AC16 cardiomyocyte cultures exposed to TNFα or hyperglycemic conditions. A similar suppressive effect on NF-κB activation and pro-inflammatory cytokine expression was also seen in cardiomyocytes by knocking down the expression of GSK3β. NF-κB activity was restored in REDD1-deficient cardiomyocytes exposed to hyperglycemic conditions by expression of a constitutively active GSK3β variant. In the hearts of diabetic mice, REDD1 was required for reduced inhibitory phosphorylation of GSK3β at S9 and upregulation of IL-1β and CCL2. Diabetic REDD1+/+ mice developed systolic functional deficits evidenced by reduced ejection fraction. By contrast, REDD1-/- mice did not exhibit a diabetes-induced deficit in ejection fraction and left ventricular chamber dilatation was reduced in diabetic REDD1-/- mice, as compared to diabetic REDD1+/+ mice. Overall, the results support a role for REDD1 in promoting GSK3β-dependent NF-κB signaling in cardiomyocytes and in the development of cardiac function deficits in diabetic mice.
摘要：
心肌细胞中转录因子NF-κB的激活与糖尿病引起的心脏功能缺陷的发展有关。NF-κB控制一系列促炎细胞因子和趋化因子的表达。我们最近发现，在发育和DNA损伤反应1（REDD1）中调节的应激反应蛋白是糖尿病小鼠心脏中促炎细胞因子表达增加所必需的。本文的研究被设计为通过研究REDD1在心肌细胞中NF-κB信号传导中的作用来扩展先前的报道。REDD1基因缺失抑制了暴露于TNFα或高血糖条件的人AC16心肌细胞培养物中NF-κB信号传导和转录因子的核定位。通过降低GSK3β的表达，在心肌细胞中也观察到对NF-κB活化和促炎细胞因子表达的类似抑制作用。通过表达组成型活性GSK3β变体，在暴露于高血糖条件的REDD1缺陷型心肌细胞中恢复了NF-κB活性。在糖尿病小鼠的心脏中，需要REDD1来减少GSK3β在S9的抑制性磷酸化以及IL-1β和CCL2的上调。糖尿病性REDD1+/+小鼠出现收缩功能缺陷,表现为射血分数降低。相比之下,REDD1-/-小鼠没有表现出糖尿病诱导的射血分数缺陷，并且糖尿病REDD1-/-小鼠的左心室腔扩张减少，与糖尿病REDD1+/+小鼠相比。总的来说,结果支持REDD1在促进心肌细胞GSK3β依赖性NF-κB信号传导和糖尿病小鼠心脏功能缺陷发展中的作用.
