title: 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.
authors.affiliation: Emergency Department, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, 250014, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Department of Health, Qingdao Municipal Hospital, No.5 Donghaizhong Road, Qingdao, 266071, Shandong, China. zhaohaodekeyan@163.com.
authors.forename: Ruijuan
authors.initials: R
authors.lastname: Shen
authors.affiliation: Emergency Department, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, 250014, China.
authors.forename: Xiaobin
authors.initials: X
authors.lastname: Dong
authors.affiliation: Department of Health, Qingdao Municipal Hospital, No.5 Donghaizhong Road, Qingdao, 266071, Shandong, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Shen
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005355:Fibrosis / Q000188:drug therapy*; D006331:Heart Diseases / Q000188:drug therapy*; D020672:I-kappa B Proteins / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology* / Q000627:therapeutic use; D007249:Inflammation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000150:complications*; D058628:Myofibroblasts / Q000473:pathology; D016328:NF-kappa B / Q000187:drug effects* / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology* / Q000627:therapeutic use; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D015996:Survival Rate
chemical_list: D020672:I-kappa B Proteins; D007093:Imidazoles; D016328:NF-kappa B; D010879:Piperazines; C482205:nutlin 3; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2
keywords: MDM2; NF-κB; fibrosis; inflammation; myocardial infarction