Murine Double Minute-2 Inhibition Attenuates Cardiac Dysfunction and Fibrosis by Modulating NF-κB Pathway After Experimental Myocardial Infarction

Abstract—Inflammation has been implicated in myocardial infarction (MI). MDM2 associates with n- uclear factor-κB(NF-κB)-mediated inflammation. However, the role ofMDM2 inMI remains unclear. This study aimed to evaluate the impacts ofMDM2 inhibition on cardiac dysfunction and fibrosis after experimentalMI and the underlying mechanisms. Three-month-old male C57BL/6 micewere subjected to left anterior descending (LAD) coronary artery ligation for induction of myocardial infarction (MI). Immediately afterMI induction, mice were treated withNutlin-3a (100 mg/kg) or vehicle twice daily for 4 weeks. Survival, heart function and fibrosis were assessed. Signaling molecules were detected by Western blotting. Mouse myofibroblasts under oxygen and glucose deprivation were used for in vitro experiments. MDM2 protein expression was significantly elevated in the mouse heart after MI. Compared with vehicle-treated animals, Nutlin-3a treatment reduced the mouse mortality. Nutlin-3a treatment improved heart function and decreased the infarct scar and fibrosis compared with vehicle. Furthermore, MDM2 inhibition restored IκB and inhibited NF-κB activation, leading to suppressed production of proinflammatory cytokines in the heart after MI. The consistent results were obtained in vitro. MDM2 inhibition reduced cardiac dysfunction and fibrosis after MI. These effects of MDM2 inhibition is mediated through modulating NF-κB activation, resulting in inhibition of inflammatory response.