Nuclear receptor NR4A2 is upregulated with cardiac surgery and triggers spontaneous arrhythmias in mice

Postoperative arrhythmias (POAs) are a common complication of cardiac surgery and a major cause for in-hospital morbidity and mortality. Nuclear receptor subfamily 4 group A member 2 (NR4A2) is an immediate-early response gene induced by inflammation and catecholamines, two well-known contributors of POAs. Here we aimed to elucidate the impact that open-heart surgery exerts on cardiac NR4A2 expression, and to determine the consequences for cardiomyocyte physiology and heart rhythm. First, using a novel NR4A2 monoclonal antibody, the comparison of left ventricular tissue samples from donor individuals and cardiac surgery patients confirmed that NR4A2 is induced in the heart during the perioperative period. Next, male and female mice with inducible, cardiomyocyte-specific overexpression of NR4A2 were found to develop arrhythmias within a timeframe consistent with the incidence of POAs. Three days after NR4A2 induction, ventricular myocytes exhibited a transcriptional down-regulation of several proteins critical for dyads formation. This was linked to the deregulation of a large network of non-coding RNAs governing cardiac development, including the down-regulation of the muscle-specific microRNAs (miRNAs) miR-133a and miR-499, and the up-regulation of a supercluster of 36 miRNAs encoded by a paternally imprinted polycistronic transcript located within the Dlk1-Dio3 locus. Short hairpin RNA (shRNA)-mediated knockdown of the polycistronic transcript initiated prior to NR4A2 induction was sufficient to partially restore the expression of critical dyad components and attenuate the occurrence of arrhythmias. In conclusion, our findings expose NR4A2 as a novel proarrhythmogenic substrate and a potential new target for the treatment of POAs in cardiac surgery patients.