Ge Zhi-Dong, Lian Qingquan, Mao Xiaowen, Xia Zhengyuan
Department of Anesthesiology, The Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University, Wenzhou.
Department of Anesthesiology, Medical College of Wisconsin, Milwaukee.
Int Heart J. 2019 May 30;60(3):512-520. doi: 10.1536/ihj.18-476. Epub 2019 Apr 10.
Diabetic cardiomyopathy is one of the main causes of heart failure and death in patients with diabetes mellitus. Reactive oxygen species produced excessively in diabetes mellitus cause necrosis, apoptosis, ferroptosis, inflammation, and fibrosis of the myocardium as well as impair the cardiac structure and function. It is increasingly clear that oxidative stress is a principal cause of diabetic cardiomyopathy. The transcription factor nuclear factor-erythroid 2 p45-related factor 2 (NRF2) activates the transcription of more than 200 genes in the human genome. Most of the proteins translated from these genes possess anti-oxidant, anti-inflammatory, anti-apoptotic, anti-ferroptotic, and anti-fibrotic actions. There is a growing body of evidence indicating that NRF2 and its target genes are crucial in preventing high glucose-induced oxidative damage in diabetic cardiomyopathy. Recently, many natural and synthetic activators of NRF2 are shown to possess promising therapeutic effects on diabetic cardiomyopathy in animal models of diabetic cardiomyopathy. Targeting NRF2 signaling by pharmacological entities is a potential approach to ameliorating diabetic cardiomyopathy. However, the persistent high expression of NRF2 in cancer tissues also protects the growth of cancer cells. This "dark side" of NRF2 increases the challenges of using NRF2 activators to treat diabetic cardiomyopathy. In addition, some NRF2 activators were found to have off-target effects. In this review, we summarize the current status and challenges of NRF2 as a potential therapeutic target for diabetic cardiomyopathy.
糖尿病性心肌病是糖尿病患者心力衰竭和死亡的主要原因之一。糖尿病中过度产生的活性氧会导致心肌坏死、凋亡、铁死亡、炎症和纤维化，并损害心脏结构和功能。越来越清楚的是，氧化应激是糖尿病性心肌病的主要原因。转录因子核因子红系2 p45相关因子2（NRF2）可激活人类基因组中200多个基因的转录。这些基因翻译产生的大多数蛋白质都具有抗氧化、抗炎、抗凋亡、抗铁死亡和抗纤维化作用。越来越多的证据表明，NRF2及其靶基因在预防糖尿病性心肌病中高糖诱导的氧化损伤方面至关重要。最近，许多天然和合成的NRF2激活剂在糖尿病性心肌病动物模型中显示出对糖尿病性心肌病有有前景的治疗作用。通过药物实体靶向NRF2信号通路是改善糖尿病性心肌病的一种潜在方法。然而，NRF2在癌组织中的持续高表达也保护癌细胞的生长。NRF2的这种“阴暗面”增加了使用NRF2激活剂治疗糖尿病性心肌病的挑战。此外，发现一些NRF2激活剂有脱靶效应。在这篇综述中，我们总结了NRF2作为糖尿病性心肌病潜在治疗靶点的现状和挑战。
