| Objective: Myocardial infarction(MI)causes huge loss of life and property all over the world.Although reperfusion therapy can help patients with coronary heart disease avoid acute death,abnormal or excessive cardiac remodeling after myocardial infarction is detrimental to survivals.Excessive occurrence and development of reactive fibrosis outside the infarct area will lead to progressive damage to the structure and function of the heart and eventually lead to arrhythmias or heart failure.Mitochondrial division inhibitor 1(Mdivi-1)has been shown to play a beneficial role in a variety of diseases by inhibiting dynamin-related protein 1(Drp1)mediated mitochondrial fission.However,the effect of Mdivi-1 on fibrosis at the edge of myocardial infarction and its possible mechanism remain unclear.In this study,in vitro and in vivo experiments were conducted to verify the therapeutic effect of Mdivi-1 on fibrosis in infarcted border zone after myocardial infarction,and to explore its potential mechanism of action.Methods: In vitro,NIH3T3 cells were induced by TGF-β1(10 ng/m L)and then were treated with Mdivi-1(25 μM).Transdifferentiation,proliferation and collagen production of cells were detected by immunofluorescence,cell counting kit-8 and western blot,respectively.In vivo,C57BL/6 mice were randomly divided into 6 groups(9 mice in each group): Sham operation group(Sham),Sham operation+Mdivi-1 administration group(Mdivi-1),7-day myocardial infarction group(MI7d),14-day myocardial infarction group(MI14d),28-day myocardial infarction group(MI28d),28-day myocardial infarction +Mdivi-1 administration group(MI28d+Mdivi-1).Myocardial infarction model was established by ligation of the left anterior descending coronary artery.Mice in Mdivi-1 and MI28d+Mdivi-1 groups were intraperitoneally injected with Mdivi-1(1 mg/kg)every other day,starting from the second day after surgery until the mice were sacrificed on the28 th day.Level of fibrosis,cardiac function,expression of type I collagen and α smooth muscle actin,mitochondrial fission and oxidative stress were assessed by Masson trichrome stain,transthoracic cardiac ultrasound,pressure-volume cardiac catheterization,western blot,transmission electron microscopy and Dihydroethidium staining,respectively.Besides,fluorescence staining of mitochondrial,q RT-PCR,bioinformatics analysis,si RNA transfection and other methods were used to explore the mediating mechanism of Mdivi-1.Results: In vitro,the expression of type I collagen and α smooth muscle actin was increased in NIH3T3 cells under the stimulation of TGF-β1,and the proliferation of cells was increased.Mdivi-1 significantly reversed these changes of NIH3T3 cells induced by TGF-β1.In vivo,Mdivi-1 significantly reduced the transdifferentiation,collagen production of fibroblast and fibrosis in the infarcted border zone of myocardial infarction,and improved the function of impaired heart.In addition,in vivo and in vitro experiments have shown that mitochondrial fission of fibroblast or myofibroblast in the infarcted border zone was increased after MI.Mdivi-1 decreased the phosphorylation of Drp1 at Ser616 and mitochondrial fission of fibroblast or myofibroblast in the infarcted border zone.Besides,Mdivi-1 significantly increased the expression of Heme oxygenase 1(Hmox1)in fibroblasts and alleviated oxidative stress.Conclusion: This study indicates that Mdivi-1 can inhibit Drp1-mediated mitochondrial fission in fibroblasts in the peripheral area of infarction after MI,reduce the transdifferentiation,proliferation,collagen production of fibroblasts and the fibrosis in the peripheral area of infarction,and partially improve the impaired cardiac function.In addition,regulation of Hmox1 protein and oxidative stress may be another potential mechanism that mediates the effects of Mdivi-1.This study provides a new idea and theoretical basis for Mdivi-1 in the treatment of fibrosis in peripheral area after MI. |
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