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 nuclear factor-κB (NF-κB)-mediated inflammation. However, the role of MDM2 in MI remains unclear. This study aimed to evaluate the impacts of MDM2 inhibition on cardiac dysfunction and fibrosis after experimental MI and the underlying mechanisms. Three-month-old male C57BL/6 mice were subjected to left anterior descending (LAD) coronary artery ligation for induction of myocardial infarction (MI). Immediately after MI induction, mice were treated with Nutlin-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.

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“…MDM2 overexpression has been observed in other diseases, including SLE and LN, pSS, FXS, RSH, atherosclerosis, MI, TAD, ARCI, and pterygium . Interestingly, MDM2 could be differentially expressed in different stages of the disease.…”

“…MDM2 exerts a role in myocardial infarction (MI) by regulating inflammation in a p53‐dependent manner (Figure ) . Zhao et al have observed increased protein expression of MDM2 in the cardiac tissue of mice after the induction of MI.…”

“…MDM2 exerts a role in myocardial infarction (MI) by regulating inflammation in a p53‐dependent manner (Figure ) . Zhao et al have observed increased protein expression of MDM2 in the cardiac tissue of mice after the induction of MI. In this MI mouse model, the pharmacological inhibition of MDM2 by nutlin‐3a (100 mg/kg, oral) improved the cardiac function, reduced the infarct scar and fibrosis, and decreased the mortality of mice .…”

“…Zhao et al have observed increased protein expression of MDM2 in the cardiac tissue of mice after the induction of MI. In this MI mouse model, the pharmacological inhibition of MDM2 by nutlin‐3a (100 mg/kg, oral) improved the cardiac function, reduced the infarct scar and fibrosis, and decreased the mortality of mice . Subsequent studies have indicated that nutlin‐3a treatment reactivates IκB, causes NFκB inactivation, and inhibits the production of proinflammatory cytokines in the post‐MI heart .…”

“…In this MI mouse model, the pharmacological inhibition of MDM2 by nutlin‐3a (100 mg/kg, oral) improved the cardiac function, reduced the infarct scar and fibrosis, and decreased the mortality of mice . Subsequent studies have indicated that nutlin‐3a treatment reactivates IκB, causes NFκB inactivation, and inhibits the production of proinflammatory cytokines in the post‐MI heart . Schreckenberg et al have found that immediately following MI, rapid and transient G‐protein‐coupled receptor kinase 2 (GRK2) activation may exert a protective effect against cardiac injury due to excessive stress.…”