Murine Double Minute-2 Inhibition Attenuates Cardiac Dysfunction and Fibrosis by Modulating NF-κB Pathway After Experimental Myocardial Infarction
Murine Double Minute-2 Inhibition Attenuates Cardiac Dysfunction and Fibrosis by Modulating NF-κB Pathway After Experimental Myocardial Infarction
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DOI：
10.1007/s10753-016-0473-5
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发表时间：
2017-02
期刊：
影响因子：
5.1
通讯作者：
Hao Zhao;Ruijuan Shen;Xiao-bin Dong;Yi Shen
中科院分区：
文献类型：
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作者：
Hao Zhao;Ruijuan Shen;Xiao-bin Dong;Yi Shen
炎症与心肌梗死(MI)有关。MDM2与核因子-κB(NF-κB)介导的炎症有关。然而，MDM2在心肌梗死中的作用尚不清楚。本研究旨在评价抑制MDM2对实验性心肌梗死后心功能不全和纤维化的影响及其机制。3月龄雄性C57BL/6小鼠结扎左前降支(LAD)诱导心肌梗死(MI)。心肌梗死后立即给予Nutlin-3a(100 mg/kg)或赋形剂，每日2次，连续4周。评估患者的存活率、心功能和纤维化程度。Western blotting检测信号分子。用缺氧缺糖条件下的小鼠肌成纤维细胞进行体外实验。心肌梗死后小鼠心脏组织中MDM2蛋白表达显著升高。与赋形剂处理的动物相比，Nutlin-3a处理降低了小鼠的死亡率。与赋形剂相比，Nutlin-3a治疗改善了心功能，减少了梗死瘢痕和纤维化。此外，抑制MDM2使IκB恢复，并抑制NF-κB的激活，从而抑制MI后心脏促炎性细胞因子的产生。在体外获得了一致的结果。抑制MDM2可减少心肌梗死后心功能不全和纤维化。MDM2的这些抑制作用是通过调节NF-κB的激活而介导的，从而抑制了炎症反应。
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 forin vitroexperiments. 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 obtainedin 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.