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-kappa B (I kappa B) signaling by decreasing I kappa B alpha 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-kappa B activation was almost completely abolished by the JAK2 inhibitor AG490, indicating that NR4A3 prevented serum deprivation induced NF-KB activation in a STAT3 dependent manner. These findings provide novel evidence that NR4A3 could inhibit post-AMI inflammation responses via JAK2-STAT3/NF-kappa B signaling and may well be a therapeutic target for cardiac remodeling after AMI. (C) 2019 Elsevier Inc. All rights reserved.