Department of Physical Emergency, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.
Nursing Management Department, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, China.
Biochem Biophys Res Commun. 2019 Oct 1;517(4):697-702. doi: 10.1016/j.bbrc.2019.07.116. Epub 2019 Aug 6.
Inflammatory responses play a critical role in left ventricular remodeling after acute myocardial infarction (AMI). NR4A3, a member of the NR4A orphan nucleus receptor family, has recently emerged as a therapeutic target for treatment of inflammation. This aim of this study is to explore the therapeutic effect of NR4A3 in cardiac remodeling post AMI. Male C57BL/6 mice were administered with lentiviral over-expression of NR4A3 (lenti-NR4A3) or empty vector (lenti-con) 7 days before coronary artery ligation. H9c2 cardiomyocytes deprived of serum were used to mimic ischemic conditions in vivo. Lenti-NR4A3 treatment significantly repressed neutrophil infiltration in the myocardium, reduced infarct size, and attenuated the reduction of left ventricular function after AMI. Furthermore, NR4A3 over-expression inhibited the NF-κB (IκB) signaling by decreasing IκBα phosphorylation and by inhibiting the translocation of p65 to the nucleus. Meanwhile, NR4A3 over-expression also increases the activity of JAK2-STAT3 signaling in mouse hearts after AMI. The inhibitory effect of NR4A3 on NF-κB activation was almost completely abolished by the JAK2 inhibitor AG490, indicating that NR4A3 prevented serum deprivation induced NF-κB activation in a STAT3 dependent manner. These findings provide novel evidence that NR4A3 could inhibit post-AMI inflammation responses via JAK2-STAT3/NF-κB signaling and may well be a therapeutic target for cardiac remodeling after AMI.
炎症反应在急性心肌梗死（AMI）后左心室重构中起着关键作用。NR4A3 是 NR4A 孤儿核受体家族的成员之一，最近已成为治疗炎症的治疗靶点。本研究旨在探讨 NR4A3 在 AMI 后心脏重构中的治疗作用。雄性 C57BL/6 小鼠在冠状动脉结扎前 7 天给予过表达 NR4A3 的慢病毒（lenti-NR4A3）或空载体（lenti-con）。H9c2 心肌细胞被剥夺血清以模拟体内缺血条件。Lenti-NR4A3 治疗显著抑制心肌中性粒细胞浸润，减少梗死面积，并减轻 AMI 后左心室功能的降低。此外，NR4A3 过表达通过减少 IκBα 磷酸化和抑制 p65 向核内易位来抑制 NF-κB（IκB）信号。同时，NR4A3 过表达还可增加 AMI 后小鼠心脏中 JAK2-STAT3 信号的活性。JAK2 抑制剂 AG490 几乎完全消除了 NR4A3 对 NF-κB 激活的抑制作用，表明 NR4A3 通过 STAT3 依赖性方式防止血清剥夺诱导的 NF-κB 激活。这些发现为 NR4A3 通过 JAK2-STAT3/NF-κB 信号抑制 AMI 后炎症反应提供了新的证据，并且可能是 AMI 后心脏重构的治疗靶点。
