Bmal1过表达对动脉粥样硬化斑块病变程度及稳定性的影响

Effect of Bmal1 gene overexpression on the degree of atherosclerosis and plaque stability

目的:探讨昼夜节律基因脑肌类芳烃受体核转位样蛋白1(Bmal1)过表达对小鼠动脉粥样硬化斑块病变程度及斑块稳定性的影响。方法:12只血管平滑肌细胞特异性Bmal1转基因的SM-Bmal1-TG/ApoE^(-/-)小鼠和12只ApoE^(-/-)小鼠均予以高脂饮食,行颈总动脉CAST套管结扎术使小鼠形成动脉粥样硬化斑块。喂养11周后处死动物,取出颈总动脉血管,行苏木精-伊红染色检测小鼠主动脉粥样硬化程度及斑块面积,Western blot法检测及基质金属蛋白酶(MMP)-2、MMP-9的蛋白表达水平。结果:与ApoE^(-/-)组相比,SM-Bmal1-TG/ApoE^(-/-)组三酰甘油(TC)、总胆固醇(TG)、低密度脂蛋白胆固醇(LDL-C)水平均明显降低(P均<0.05),2组高密度脂蛋白胆固醇(HDL-C)水平的差异无统计学意义。SM-Bmal1-TG/ApoE^(-/-)组小鼠颈总动脉斑块减少约25%,内膜增厚不明显。与ApoE^(-/-)组相比,SM-Bmal1-TG/ApoE^(-/-)组MMP-2、MMP-9的蛋白表达水平均明显降低(P均<0.05)。结论:Bmal1可抑制动脉粥样硬化斑块病变程度,下调主动脉粥样斑块内MMP-2、MMP-9水平,具有抗动脉粥样硬化的作用。

Objective:To investigate the effect of circadian rhythm gene BMAL1 on the degree of atherosclerosis and plaque stability.Methods:BMAL1 overexpression mice(SMBmal1-TG/ApoE^(-/-))and ApoE^(-/-)mice were treated with high-fat diet,and atherosclerotic plaque was created by carotid artery ligation with a CAST cannula.All animals were then sacrificed after 11 weeks of feeding.The whole segment of carotid artery was taken out for HE staining and western blot to determine the degree of aortic atherosclerosis.The protein expression levels of matrix metalloproteinase-2(MMP-2)and matrix metalloproteinase-9(MMP-9)were assessed.Results:Blood levels of triglyceride,total cholesterol,and low-density lipoprotein were lower in SMBmal1-TG/ApoE^(-/-)mice than those in ApoE^(-/-)mice(all P<0.05),but high-density lipoprotein level was similar in both groups.Compared with ApoE^(-/-)mice,the degree of carotid atherosclerotic plaque was decreased by 25% without obvious intimal thickening in SM-Bmal1-TG/ApoE^(-/-)mice.In addition,MMP-2 and MMP-9 levels were significantly reduced in SM-Bmal1-TG/ApoE^(-/-)mice(all P<0.05).Conclusion:This study suggests that overexpression of Bmal1 gene could inhibit the degree of atherosclerosis and exert a beneficial effect on plaque stabilization.