孤核受体Nr4a1调控单核/巨噬细胞分化和极化改善糖尿病急性心肌梗死损伤修复的机制研究

The mechanisms of weakened cardiac repair and aggravated ventricular remodeling after acute myocardial infarction (AMI) in patients with diabetes mellitus (DM) remain obscure. Our previous studies have found that the expression of Nr4a1, an orphan nuclear receptor, was decreased in monocyte / macrophage (Mo / Mφ) of diabetic mice. Recent studies found that activation of Nr4a1 promoted anti-inflammatory differentiation of Mo and induced M2 polarization of Mφ in vitro, improved ventricular remodeling in mice with AMI in vivo. However, its effects on the injury repair following AMI in mice with DM have not yet been illuminated..In this study, we will investigate that: (A) the mechanism of decreased expression of Nr4a1 in Mo / Mφ in high glucose environment (high glucose induced hypermethylation of Nr4a1 gene?); (B) the mechanism of Nr4a1 regulating differentiation of Mo (through Nr4a1/CEBPα axis?) and polarization of Mφ (via Nr4a1/ TGF-β/ TGF-βR/ PPARγ pathway?), and the effects of Nr4a1 on phagocytosis and angiogenesis of Mφ; (C) the regulation of Nr4a1 on the differentiation, polarization of Mo / Mφ and cardiac repair using an AMI model in mice with DM. It is hoped that seeking the effect and mechanism of Mo / Mφ on cardiac repair post AMI in diabetic mice utilizing Nr4a1 as an entry point would provide a novel target for the improvement of myocardial repair in diabetic patients with AMI.

糖尿病患者急性心肌梗死(AMI)后心肌修复减弱，心室重构加重，但机制不明。我们发现糖尿病小鼠单核/巨噬细胞（Mo/ Mφ）孤核受体Nr4a1表达降低。新近发现，激活Nr4a1：体外可促进Mo向抗炎型分化，诱导Mφ向M2极化；体内可改善小鼠AMI后心室重构。但其对糖尿病AMI后损伤修复的影响尚不明确。.本项目拟探讨：①高糖环境Mo/Mφ表达Nr4a1降低的机制（Nr4a1基因超甲基化？）；②Nr4a1影响Mo分化（影响转录因子CEBPα表达？），调控Mφ极化（通过TGF-β/TGF-βR /PPARγ轴？）及调节Mφ吞噬和促血管新生能力（通过影响MerTK和VEGF表达？）的机制；③采用糖尿病小鼠AMI模型，验证Nr4a1对Mo/Mφ分化、极化及对心肌修复的调控作用。旨在以Nr4a1为切入点，探讨糖尿病AMI后心肌修复中Mo/Mφ的作用和机制，为改善糖尿病AMI心肌修复的治疗提供新靶点。

本研究通过探索NR4A1在不同动物及细胞模型中的表达变化，发现NR4A1在糖尿病模型及急性心肌梗死模型中表达均上调，并由此提出研究NR4A1在糖尿病心梗中的作用及机制的研究思路。本研究发现糖尿病心梗后因炎症反应加剧及心肌纤维化加重而导致心功能障碍进一步恶化，阐明了NR4A1过表达可减弱糖尿病心梗后的炎症反应并减轻心肌纤维化的内在机制，验证了NR4A1通过抑制NF-κB的磷酸化激活而抑制糖尿病心梗后的炎症反应，证明了NR4A1对小鼠糖尿病心梗后的心肌损伤具有保护作用。