Effect Of Clock Gene Bmal1 Knockout On Myocardial Fibrosis In Diabetic Mice

Objective: To investigate the effect of knockout of Bmal1 on myocardial fibrosis in rat model of diabetes.Methods:Wild type C57/B6 mice and Bmal1 knockout mice(n=24)were randomly divided into 4 groups(n=6);WT group,WT-DM group,KO group,KO-DM group.Type 1 DM mouse model was established by intraperitoneal injection of streptozotocin(STZ)at a dose of 50mg/kg/ day for 5 days.The age-and sex-matched controls were intraperitoneally injected with the same volume of PBS solution.Eight weeks later,Echocardiography was used to evaluate heart function,HE and Masson staining methods were used to observe the collagen distribution and collagen volume fraction was measured by image analysis.The expression levels of TGF-β1 和 Smad 2、MMPl/TIMPl、MMPl3和 MMPl4 in the cardiac tissues were determined by western blotting.Results:1.Compared with WT group,the body weight of mice in WT-DM group decreased and blood glucose increased after model formation(P < 0.05);Compared with WT-DM group,the body weight of mice in KO-DM group decreased and blood glucose increased after model formation(P < 0.05);2.Compared with WT-DM group,collagen expression in muscle tissue of mice in KO-DM group was increased,myocardial interstitial fibrosis was observed,left ventricular short axis shorting rate(FS)was decreased,ejection fraction(EF)and cardiac output(CO)were decreased,and heart stroke volume(SV)was decreased(P<0.05);3.Compared with WT,BMAL1 protein expression was decreased,TGF-β1 and Smad2 higher expression,MMPl/TIMPl ratio significantly change,MMP13 increased,the content of MMP14 expression(P<0.05).Conclusions:Bmal1 knockout can aggravate STZ-induced myocardial fibrosis in rat model of diabetes,which may be mediated by the activation of TGF-β/Smad2 pathway.